ISSUE 330
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The application aims to investigate endometrial cancers with regard to new molecular classifications. The ENCORE project studies real-world survival based on molecular patterns, analyzes the immune environment of tumors with concurrent p53 mutations, and correlates the eosinophil to lymphocyte ratio with patient outcome. In addition, the relevance of hormone and HER2 receptors in the individual molecular subtypes is examined.
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Indirect capping of the dental pulp is recommended in deep cavities, but there is little clinical evidence for the success of the procedure. In an innovative simulation model of the pulp-dentin-complex, the effect of different biocompatible capping materials on human pulp cells through a dentin barrier will be tested. By analyzing cell survival, gene expression, oxidative stress and cytokine production, their bioactive effects will be compared in a way that is not possible in vivo.
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Chondrosarcomas are malignant bone tumors, which do not respond to existing chemo- and radiotherapy. Preliminary studies could show that the the natural compound Garcinol strongly reduces proliferation and colony formation of these tumor cells. Additionally, Garcinol could re-sensitize chondrosarcoma cells to the chemotherapeutic Cisplatin. We therefore want to investigate the role of Garcinol as a new therapeutic option for chondrosarcoma.
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The proposed project will investigate the effect of common therapies such as hydroxychloroquine, tocilizumab, mycophenolate mofetil or rituximab in systemic lupus and systemic sclerosis patients. Closing a major gap in our knowledge of how distinct therapies influence T cell differentiation, metabolic reprogramming, subsets distribution and effector functions; this study will guide the improvement of disease management to favour immune competence.
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The project aims to explore differences in how neonatal and adult intestinal epithelial cells respond to microbial metabolites. As the first line of immune defense, epithelial cells regulate the balance between tolerance and immune responses. The impact of bacterial colonization on gut maturation is poorly understood but may shape future immune responses. This study will shed light on how early-life events influence immune development and their role in autoimmune diseases like IBD, MS, and SLE.
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HCMV glycoprotein B variants are being studied with respect to viral fusion and syncytium formation. The specific objectives are: (1) identification of polymorphisms that enhance or inhibit fusion; (2) characterization of the fusion phenotype of these viruses in different cell lines; and (3) development of a murine CMV with hyperfusogenic gB. This study aims to understand the regulation of gB fusion activity and to identify potential diagnostic markers for HCMV pathogenicity.
The aim of this project is to better understand the influence of T cells and the NLRP3 inflammasome in the context of multiple system atrophy (MSA). Therefore, an already established transgenic mouse model and human brain tissue from MSA patients will be used. The aim is to lay the groundwork for further projects using T cells and NLRP3 as potential pharmacological targets for MSA treatment.
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In a subgroup of patients with Post-COVID Syndrom (PCS), functional autoantibodies against G protein-coupled receptors (GPCR-fAAbs) occur. We would like to characterise changes in the immune cell compartment of these patients, as we have seen changes of certain immune cells in preliminary experiments. Furthermore, we seek to analyse the effect of the substance BC 007, which can neutralize GPCR-fAAbs, in ex-vivo and in-vitro experiments.
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Gait impairment as a common and real-life-relevant symptom in Parkinsons disease may be objectively and quantitatively detected by digital technologies in and outside the hospital. In this project, we aim to comprehensively analyse digital mobility data gained in a large multicenter study with regard to detecting objective mobility outcomes for describing the disease course (disease progression or therapy response) in a cohort of PD patients (n=130). All datasets are available.
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This project aims to develop lipid nanoparticle (LNP) vaccines for targeted delivery of HIV-1 antigens and checkpoint inhibitors (CPI) mRNA. By displaying HIV-1 antigens on the LNP surface, we seek to efficiently target and activate Env-specific B cells. Concurrent delivery of CPI mRNA into the cells is anticipated to induce local checkpoint inhibitor production, modulating immune response without systemic CPI exposure.
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The aim of the planned project is to investigate the effect of NPWT on the cell lines involved in wound healing and on the cells generally found in the skin. Keratinocytes, melanocytes, fibroblasts, endothelial cells and ADSCs will be cultivated in combination with NPWT under dynamic conditions (continuous medium flow via a peristaltic pump). Under optimal cultivation conditions, the effects of a prolonged application of negative-pressure wound therapy will be investigated.
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Lipid nanocapsules, functionalized with RGD sequence to target ?V?3 integrin receptor on podocytes and loaded with therapeutic substances will be investigated as a podocyte specific therapeutic strategy. Uptake and therapeutic potential of loaded nanoparticles to rescue proteinuric phenotypes will be investigated in different zebrafish glomerular disease models. These experiments enable in vivo analysis of nanocarriers as potential cell type specific drug delivery systems.
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Chronic stress has long-lasting effects on the hippocampal function, but it still remains unclear how. We investigate stress-induced epigenetic changes as a biological link between chronic stress and brain dysfunction. Our preliminary data has identified lamin B1 as a target of chronic stress. Lamin B1 is an epigenetic factor that maintains heterochromatin. We will investigate how chronic stress downregulates lamin B1, and how stress-induced reduction of lamin B1 affects epigenetic regulation.
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Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a fatal adult-onset neurological disease caused by pathological variants in CSF1R (colony-stimulating factor-1 receptor). As microglia are primarily affected in HDLS, we developed an iPSC-derived microglia model to study CSF1R function in healthy and HDLS patient lines. Using this model, we propose to investigate novel CSF1R interactions using APEX2-based proximity labeling focusing on transcriptional regulation.
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As a result of non-specific inhibition, tyrosine kinase inhibitors (TKIs) also affect bone and cartilage development. Children and adolescents therefore suffer from significant growth retardation during therapy. Alternative therapy concepts are therefore urgently needed. In the proposed project, the influences of different TKIs on bone metabolism and cartilage differentiation will be investigated.
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Mutations in CTBP1 cause rare neurodevelopmental syndrome HADDTS. I have shown that CTBP1 controls hippocampal energy metabolism and protects synaptic transmission from metabolic stress Notably, deletion in glia and/or neurons had distinct effects. Here, we will investigate the role of CTBP1 in neuron-glia metabolic coupling necessary for energetic and functional homeostasis in brain. The results will provide new rational basis for treatment of HADDTS.
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Various factors contribute to the pathogenesis of ulcerative colitis (UC). Importantly, telomere shortening is often observed in intestinal epithelial cells (IECs) of patients with UC. Nevertheless, the functional role telomere length in IECs is poorly understood. This project aims to evaluate how telomere length is involved in the regulation of pro-inflammatory pathways and affects the barrier integrity in patients with UC.
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In breast cancer, the success of neoadjuvant chemotherapy depends on tumor-infiltrating lymphocytes and their specificity, especially against neoantigens - promising targets for immunotherapies. 3D-cell cultures offer a more realistic representation of tumor-immune cell interactions than conventional ones. The project seeks to compare 4 T-cell receptor-based immunotherapies against neoantigens in 2D- and 3D-models, aiming to identify the most promising approach for potential future treatments.
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Although peritoneal metastasis (PM) majorly contributes to colon cancer (CC) related deaths, knowledge on its molecular mechanisms and putative markers is limited. CC tumors deficient for the transcription factor ATF2 are associated with PM. Our project aims to unravel the role of ATF2 loss during peritoneal seeding and, in particular, the effects on mesothelial cells executed by the secretome of ATF2-deficient CC cells. Thereby, novel therapeutic approaches for PM in CC might be identified.
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The focus of the present project is the effect of the human T cell leukemia virus (HTLV-1) on dendritic cells (DCs) in two models. The project focuses on the transmission of HTLV-1 to DCs across an intestinal barrier, analyzing the phenotype of DCs and the mechanism of transmission. For this purpose, two models, a 2D transwell and a 3D organs-on-a-chip model will be established. Finally, both models will be compared regarding their advantages, disadvantages and differences in the DC phenotype.
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In this project we want to analyze by which mechanisms the extracellular matrix (ECM) protein nephronectin (NPNT) is secreted. Inhibition of e. g. exocytosis and lysosomal trafficking will shed light on NPNT export and deposition in the ECM. In addition, we want to identify interaction partners of NPNT on podocytes within the superfamily of integrins and analyze the quality of these interactions both in vitro and in vivo.
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We aim to develop a voxelomic atlas of the brain. We will leverage high-resolution, multi-spectral ex-vivo imaging data from Magnetic Resonance Imaging (MRI) in combination with deep learning techniques, to compare single-voxel data between individuals. The atlas will serve as a tool to interpret single-voxel neuroanatomical variability. The project will build on preliminary work in sample preparation and data processing techniques.
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Physical activity in Fontan patients has a positive effect on cardiopulmonary capacity. Peak oxygen uptake represents the most robust predictor for morbidity and mortality in these children. It can be improved through exercise. High-intensity interval training (HIIT) represents the most efficient method, but the implementation is difficult. An App-based training represents an alternative with the possibility of providing positive feedback through a Fitness tracker.
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Protocols for detection of disseminated cancer cells (DCCs) in the lymph node (LN) need to be harmonized. Therefore, immunocytology vs. conventional ultrastaging will be compared and additional methods for isolation of DCCs for subsequent molecular analysis will be tested. Correlation of morphology with DCC-density and ploidy will be examined. The prognostic impact of the morphology of LN metastases will be investigated in archival cases. Further, DCCs in the neoadjuvant setting will be studied.
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A comprehensive molecular characterization of transcription factor dynamics in ccRCC evolution is a mandatory prerequisite for the development of personalized therapeutic interventions. Aim of this study is to define the components and interactions of oncogenic regulatory circuitries in ccRCC development with innovative NGS techniques. CRISPR/Cas-modified cell lines and patient-derived primary cells will be used to model early tumor stages and analyse epigenetic dysregulation in ccRCC evolution.
A rapid and unambiguous differential diagnosis of adrenal tumors is challenging, but of high clinical relevance. In a preliminary untargeted metabolomics study, conjugated steroids in urine were identified as potentially very promising diagnostic biomarkers. This project aims to develop a quantitative LC-MS assay for steroid conjugates in urine and plasma for a detailed investigation of their utility as diagnostic and prognostic biomarkers for adrenocortical carcinoma in a larger patient cohort.
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Despite good overall response rates, there are also high rates of resistance under immunotherapy and targeted therapy in the treatment of melanoma. Thus, new therapeutic options are needed and we need laboratory test systems to allow a prediction of treatment response by therapeutics. 3D organoids can be a promising tool in this regard. Therefore, in this project, melanoma-derived organoids are cultivated as a test platform to predict in vitro tumour therapy response in vivo.
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We hypothesize that, during inflammation, a highly motile subset of lymphocytes, including T cells, B cells and regulatory T cells migrates from the blood into the skin. The characterization of this highly motile subset would allow us to identify the migration and suppressive molecules selectively employed by these cells to reach the site of inflammation. We propose that we can engineere blood-derived immune cells with these molecules. In such a scenario, these engineered immune cells are highly…
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In previous our research, higher Prevotella levels were found in rheumatoid arthritis patients´ gut. We aim to define mechanisms increasing arthritis incidence by Prevotella intestinalis in murine model. We hypothesize that outer membrane vesicles of P. intestinalis disrupt the epithelial barrier, leading to a reduction of IL-18 levels. This disruption allows dendritic cells, primed by the P. intestinalis, to play a pivotal role in triggering Th17 cell-mediated arthritis in mice.
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Periodontitis (PA) is a highly prevalent disease that has bidirectional associations with Diabetes and Alzheimer's disease. PA is leading to irreversible destruction of tooth-surrounding tissues and tooth loss. The pathogenesis of PA is poorly understood. Aim is the analysis of possible Th17/Treg disbalance in PA, association with pro- and anti-inflammatory cytokines, and whether these alterations are local or systemic. The goal is to identify biomarkers and potential targets for immunotherapy.
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My preliminary data highlight that neutrophil phenotypes define distinct SLE patients and that LAMP-1 is a strongly dysregulated protein in SLE. I hypothesize that LAMP1 expression defines a distinct activation state of neutrophils associated with a clinical subgroup of SLE patients with more severe kidney involvement. Hence, this project aims to study the functional role of LAMP1 in neutrophils and probe associations of LAMP1 expression and serum levels with clinical features in SLE.
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Our preliminary study demonstrated protective effects of 3-indolepropionic acid (IPA) on the severity of CIA arthritis in mice. Our project will now I) provide insight into general IPA effects on overall brain function at rest and II) use (thermal) fMRI to evaluate central nociception as a functional readout parameter for RA severity. III) We will assess whether long-term IPA treatment up to day 35 may have additional benefits on disease progression.
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Colorectal cancer is the second leading cause of cancer-related deaths in developed countries. Our preliminary results underscore the significant role of the type I IFN-STAT2 pathway in driving necroptotic epithelial cell death, colonic inflammation, colorectal cancer progression, and resistance to anti-cancer drugs. We aim to elucidate the detailed mechanisms behind these findings. This understanding is crucial for developing innovative strategies for managing colorectal cancer in patients.
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The etiology of ALS, a fatal neurodegenerative disease, remains unclear. Our research focuses on the 'dying-back' mechanism, where neuron degeneration starts from synapses/axons. We aim to study if faulty mRNA splicing causes RNA mislocalization in axons and synapses, potentially exacerbating this mechanism by making use of iPSC-derived motor neurons from ALS apteints andd APEX2 RNA-proximity labeling in neuronal compartments.
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My preliminary results suggest that ERBB2 is upregulated in SCLC during metastasis and resistance to immune checkpoint blockade (ICB), helping the tumor to escape the immune system. We plan to investigate ERBB2 inhibitors regarding their immunoregulatory properties ex vivo in precision cut tissue slices (PCTS) and in a SCLC mouse model. We will elucidate the underlying molecular mechanisms downstream of ERBB2 and identify patients who may benefit from an ERBB2 targeted therapy.
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RA is a chronic inflammatory autoimmune disease that results in hyperplasia of synovial membrane of joints. However, little is known about the molecular profile and heterogeneity of infiltrating immune cells as well as about the molecular features of their cell-cell interactions. The aim of this project is to generate combined datasets on the molecular features and spatial distribution of resident and infiltrating immune cells via spatial transcriptomics of synovial tissue biopsies.
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We identified a new configuration of the Wnt signaling mechanism at the luminal membrane of the kidney tubule. Thus, tubular cell culture and zebrafish models are used to further investigate how Wnt ligands activate b-catenin in the tubule, and in particular how this affects the intercalated cells of the collecting duct, a cell type important for acid-base regulation. The findings resulting from these efforts could help to identify tubular targets in the therapy of nephrotic syndrome.
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Lichen sclerosus (LS) is a chronic, inflammatory, scarring disease of the skin, manifesting mostly in the genital region, that can occur at any age and in both sexes. The etiology and pathophysiology of LS remain unknown. The aim of our study is to investigate the expression of miRNAs in the tissue of patients with histologically confirmed LS in all ages and in both sexes. Histological samples from patients without evidence of LS will serve as a control group.
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MAGOH is part of the exon junction complex that binds to mRNA and regulates alternative splicing or mRNA degradation via "nonsense mediated decay". This project investigates the role of MAGOH in malignant melanoma. Preliminary data showed that a loss of MAGOH leads to cell death in melanoma cells, which will be further investigated in different melanoma cell lines, as well as healthy cells. Furthermore, the molecular mechanisms leading to the reduced viability will be analyzed.
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Osteoclasts (OCs) play key roles in the regulation of bone mass and excessive osteoclastogenesis is involved in joint destruction in autoimmune arthritis or osteoporosis. The current knowledge on cellular metabolism and its impact on OC function and bone homeostasis remain unclear. In this project, we aim to characterize metabolic dynamics during osteoclastogenesis and to identify novel regulators of bone turnover.
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Propionate is produced by the gut microbiota and has anti-inflammatory properties. Our preliminary data shows that bacterial histamine production is increased upon propionate treatment. Histamine is able to induce rapid resolution of peripheral inflammation in arthritic mice via the activation of H3 receptor, which is mainly expressed on cells of the central nervous system (CNS). In this project we aim to unravel the role of the CNS in mediating histamine-induced resolution of inflammation.
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In orthodontics, craniofacial sutures play a central role. In the present radiological study, we would like to examine to what extent 7T-MRI images of the midface are comparable to the gold standard (CT/CBCT images). To gain a better understanding of sutural remodelling at the cellular level, cyclic pressure loads will be applied to co-cultures of fibroblasts, chondrocytes and osteoblasts in a controlled in vitro system and their gene expression will be investigated.
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During central nervous system development cells undergo a series of decisions to ultimately form highly specialized networks the structural basis for behavior and cognition. This developmental decision-making process is poorly understood, yet of high clinical relevance as its disruption can result in neurodevelopmental disorders and loss of resilience to disease in later life. The Synergy Project TRAIN: Towards Rationalizing Neurodevelopment pursues a novel concept that key decisions in neurodevelopment ar…
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This project aims at identifying the expression of the CFTR complex and functionally characterising its role in in peripheral blood mononuclear cells in the context of Cystic Fibrosis (CF). Moreover, the effects of a CFTR-modulating therapy with Elexacaftor - Tezacaftor - Ivacaftor (ETI) on immune cell function and regulation will be examined in a CFTR knock-out cell line and a CF pig model as well as primary patient-derived cells.
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ZEB1 is expressed in chemoresistant tumor cells (TCs) and cancer-associated fibroblasts (CAFs). According to our recent data, it induces replication stress (RS) which can be selectively targeted in TCs for chemo-sensitization. Furthermore, we discovered ZEB1-dependent immunosuppression in CAFs, precluding immune checkpoint therapies. As CAFs also display the ZEB1-driven RS, we now seek to target both unfavorable cell types together in an immunocompetent model to enhance therapeutic efficacy.
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Using advanced deep learning techniques based on synthetic training data, MRI reconstruction methods for quantitative susceptibility mapping (QSM) will be designed and optimized for anatomical regions outside the brain. The neural networks will be generalized for different parameters, such as magnetic field strength, and tested in the prostate, knee, and breast in volunteers and compared against conventional methods.
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The aim of this project is to facilitate the understanding of the role of extracellular vesicles (EVs) in the development and progression of Parkinsons disease (PD). EVs extracted from blood of PD patients and controls will be fractionated according to cellular origin and cargo profiling will be performed focusing on pathogenic forms of aSyn and regulatory RNAs. The results will offer deeper insights in PD-related signatures, and permit exploring the origin and transfer of pathogenic molecules.
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PU.1 controls the transcriptional network of matrix production in fibrotic fibroblasts. We have now found that PU.1 is also expressed in matrix-producing osteoblasts. In this proposal, we aim to study the PU.1 network in biopsies from patients with osteoproliferative arthritis by imaging mass cytometry, to dissect PU.1-driven transcription in human osteoblastogenic cultures by ATTAC/CHIP/RNA-seq, and to use a novel osteoblast-targeting PU.1 inhibitor in experimental osteoproliferative arthritis.
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Cell trafficking is crucially involved in the pathogenesis of immune-mediated inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease. While the contribution of cell surface receptors to such trafficking has been explored in detail and has already lead to therapeutic applications, cell-intrinsic properties affecting the cellular migratory behavior have largely been overlooked. Here, we hypothesize that cell mechanical properties and cell trafficking are inextricably linked.…
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Intestinal fibrosis is a common complication in IBD with an unmet need to develop therapy options. Recent studies turned fibroblasts into the spotlight of IBD research as they are associated with fibrosis, control of inflammation and personalized therapy. Published own work showed a major role of IL36R signaling during the perpetuation of intestinal inflammation/fibrosis. This project aims to understand the role of stromal IL36R signaling for the resolution of intestinal inflammation/fibrosis.
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T cells play a key role in IBD, but the impact of Stat5 in CD4+ T cells for chronic colitis is unclear so far. Based on preliminary data demonstrating spontaneous chronic colitis in conditional Stat5 KO mice and decreased Stat5 expression in IBD, I hypothesize that Stat5 in CD4+ T cells counteracts colitis. Thus, in this project, I will explore the mechanisms and effects of CD4-specific Stat5 signalling for experimental colitis and IBD, aiming to identify novel approaches for future therapy.
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Orofacial clefts are the second-most congenital malformation. Palate development depends on cranial neural crest cells (CNCCs). CNCCs undergo diverse differentiation programs accompanied by vast changes in gene expression, to which the chromatin remodeling complexes BAF and EP400/TIP60 contribute. We will analyze the function of both complexes in iPSC-derived CNCCs in proliferation and in differentiation to tissues relevant for palatogenesis by CRISPR/Cas9-guided knockout of each central ATPase.
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A disturbed skin barrier allows for sensitization to skin-encountered allergen. Upon lung challenge with the same allergen stronger lung inflammation occurs. Preliminary data shows that basophils drive skin-mediated, allergen-specific antibody formation and we want to analyze their impact on barrier integrity and aspects of the antibody repertoire. We further plan lung-challenge of sensitized basophil deficient mice to determine functional relevance potentially critical for asthma development.
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The secretion of correctly glycosylated protective antibodies by long-lived plasma cells is essential for our immune protection. To survive and produce antibodies, long-lived plasma cells require an optimized metabolism. The aim of this study is to determine whether the glucose transporter GLUT1 plays a role in the metabolism of long-lived plasma cells and the functionality of their antibodies. Therefore, we will study a GLUT1-deficient mouse model and patients with GLUT1-deficiency syndrome.
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Protein AMPylation, which can be catalyzed by FICD, has emerged as a modulator of neurogenesis. The role of FICD-mediated AMPylation in neurodegeneration, however, has been less understood. Our preliminary data suggest a promoting function of FICD in the aggregation of alpha synuclein (aSyn), which is linked to the pathogenesis of Parkinsons diseases. This project aims to investigate the pathological relevance of FICD-mediated AMPylation in aSyn aggregation-associated neurodegeneration.
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To date, it is still obscure why in some patients with psoriasis the autoimmune process is restrained to the skin, whereas in other it extends to the joints. We will adopt models resembling psoriasis and psoriatic arthritis, with the aim of studying the joint involvement secondary to skin inflammation. The comprehension and characterization of the underlying mechanisms involved in the skin-joint axis is pivotal for a better understanding of the link between physical barriers and autoimmunity.
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The current recommendations concerning physical activity after myocarditis in the young and/or PIMS-TS are based on low evidence and are limited to the adult population. Consequently, physical activity is partly heavily restricted in a generation with an increasing sedentary live-style.We aim to evaluate in a prospective study the relationship between sport and myocarditis/PIMS-TS and the safety of the ensuing recommendations.
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Extraintestinal manifestations (EIM) are frequent in IBD patients. Our initial data revealed an osteoporosis-& PSC-like phenotype in a murine IBD model. Intestinal inflammation was linked to altered tryptophan metabolism and AHR-signalling, which are assumed to be mediators of EIM. While previous data demonstrate an impact on this pathway, mechanistic knowledge is limited. Within this project we will take advantage of 3D organ cultures to better understand the tryptophan-AHR axis in IBD and EIM.
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Aim is the development of biofabricated 3D breast cancer models, which will act as standardized tumor angiogenesis and therapy models mimicking the in vivo situation by using multiple cell types including endothelial cells as well as the supply via a perfusion bioreactor. Evaluation will be based on metabolic activity, proteomic analysis, microscopy and histology. Assessment as therapeutic model will be done using paclitaxel. Goal is the use in basic research and the improvement of therapies.
The diagnostic workup of frequent adrenocortical adenomas and rare, aggressive adrenocortical carcinomas is challenging and lacks specificity. Determination of deconjugated steroids in urine is an emerging and promising tool in this field, however, the currently best available diagnostic biomarkers provide no benefit to a third of the patients. We plan to screen the urinary metabolome by untargeted metabolomics looking for more suitable diagnostic biomarkers such as intact steroid conjugates.
Funding source: Bayerische Staatsministerien
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The role of the enteric glial cells (EGCs) in regulating mucosal immune homeostasis is largely unknown. We propose that EGC activation is tunable by cytokines and activated EGCs can shape gut immunity. Isolation, ex vivo activation, and submucosal transplantation of EGC will reveal their immunomodulatory capacity. Insights gained will reveal new avenues to curb chronic inflammation in disorders such as IBD.
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Specific regulation of protein degradation by the ubiquitin-proteasome system plays important roles in myelination, remyelination and neurodegenerative diseases. I want to analyse the functions of the deubiquitinase Otud7b in oligodendrocytes in vitro and in vivo in an oligodendrocyte-specific Otud7b knockout mouse model and identify functional targets of Otud7b in oligodendrocytes to deepen the understanding of posttranscriptional regulatory events during OL differentiation and CNS myelination.
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Constant bone remodelling is important to prevent fractures. In bones with a thick cortex, we found that remodelling is based on endosteal bone formation and periosteal resorption which stands in contrast to existing models. In this project we will characterize this process and analyse its dependence on age, mechanical load, osteoclast and osteocyte activity. We aim to explain why some bone sites are prone to fracture and to develop new treatment strategies to prevent insufficiency fracture.
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Immune cell trafficking plays a central role in the pathogenesis of ulcerative colitis (UC). Based on our preliminary data, we propose cell mechanics as an important mechanism in this process. To explore this hypothesis, we will investigate mechanisms regulating mechanics of innate immune cells in colitis models. We will further explore the functional consequences of immune cell deformability in acute colitis and explore therapeutic opportunities for a modulation of cell mechanics in UC.
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Eye rheum is a physiological ocular surface discharge contains aggregated neutrophil extracellular traps (aggNETs), indicating that neutrophils are involved in ocular surface homeostasis. In the murine model of allergic eye disease, aggNETs occlude meibomian glands causing meibomian gland dysfunction after ocular surface inflammation. Here we plan to investigate therapeutic potential of eye drops containing DNase-1 or NOX2-inhibitor to alleviate aggNETs driven ocular surface inflammation.
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We have identified the enzyme ATP Citrate Lyase (ACLY) as a key immunometabolic regulator of intestinal inflammation. We therefore hypothesize that diminished ACLY expression in the intestinal epithelium drives the pathogenesis of Inflammatory Bowel Disease. To evaluate our hypothesis, we plan to elucidate the regulation of Acly, its molecular mode of action and its functional impact for the steady-state gut and for intestinal inflammation using newly generated knockout mice.
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The function of intestinal mesenchymal cells (IMCs) in inflammatory bowel diseases (IBD) has not been clarified yet. The goal of this project is to characterize and to functionally study the role of STAT3 activation in IMCs during mucosal healing in the gut by using established in vivo models and human tissue specimens. Perspectively, these studies aim to pave the way for novel therapeutic options in IBD care.
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New medications for the treatment of chronic wounds are urgently needed. Our preliminary data show that sCD83 accelerated wound healing processes in a systemic as well as a topical treatment. Cellular analyses revealed the increase of pro-resolving macrophages, known to improve wound healing processes. These striking regenerative capacities make scD83 a promising candidate to treat chronic- and hard-to-heal wounds. Within the current project we aim to elucidate the underlying mechanisms.
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The continuous adaptation of the SARS-CoV-2 replicative machinery, as well as the consequences of nonstructural protein (Nsp) mutations to the virus-host interaction need to be considered in emerging variants. SARS-CoV-2 marker viruses will be used to address the role of existing and new variant virus mutations in Nsps in different culture systems, in viral replication and in their escape from cellular restriction, focusing on the non-spike related phenotype of these variants.
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The development of a functional central nervous system depends on the accurate coordination of the highly dynamic microtubule cytoskeleton. Here we propose to chart the molecular landscape induced by mutations in microtubule cytoskeleton components implicated in neurodevelopmental disorders in human brain organoids to uncover unifying and diverging molecular features in a tissue-like context to design strategies to interfere with disease-phenotype progression.
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We have demonstrated that the EMT-activator ZEB1 provides cancer cells not only with aberrant motility, but also with survival traits enabling tumor progression, metastasis and drug resistance. Our aim is to eliminate these aggressive untargetable EMT-state cancer cells, which strikingly show a high sensitivity to ferroptotic cell death. In this project, we want to elucidate the molecular basis of ZEB1 associated ferroptosis sensitivity to exploit it as a novel therapeutic target.
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During the course of neutrophil extracellular trap (NET) formation, intracellular calcium plays essential role in activation of enzymes like PAD-4 and calpain which are involved in chromatin decondensation. The preliminary data showed the involvement of calpain in degradation of the nuclear envelope protein nesprin. Here we will delineate the exact role of calpain in degradation of nuclear envelope protein nesprin and unfold the mechanism of nuclear membrane breakdown during NET formation.
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In this research project, the accuracy of fit of current CAD/CAM crown restorations is to be investigated using a 3D industrial scanner in order to collect scientific data on the success, durability and function of the materials for their clinical application. The fit will be determined material-dependently and also depending on the luting system used. Furthermore, the wear and thus the longevity of the restorations will be tested by means of a chewing simulator and subsequently measured in 3D.
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Intestinal diseases (IBD) are chronic inflammations of the gastrointestinal tract. Secretory antibodies (SIgA) are produced by mucosal surfaces and are intestinal defences. The project aims to elucidate the role of SIgA in the uptake/retro process at the endothelium. Furthermore, an analysis of the SIgA-selected bacterial strains in the intestine will be carried out and new targets for a SIgA-mediated therapeutic approach in therapy will be found.
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Parkinsons disease is a neurodegenerative movement disorder characterized by the progressive loss of midbrain dopaminergic (mDA) neurons. mDA neurons can be partitioned into numerous molecularly and functionally distinct neuronal subtypes. The molecular mechanisms orchestrating mDA neuron subtype specification are still largely unclear. This project will test the hypothesis that a temporal patterning program I recently uncovered contributes to the establishment of mDA neuron diversity.
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Urothelial carcinoma (UC) is among the ten most common cancers worldwide and overall therapy systemic response rates are limited (~20%). Molecular insights in processes driving therapy resistance are scarce. Here, we propose to expand our existing patient-derived living UC biobank, develop a novel zebrafish model to study the role of fatty acid metabolism and ferroptosis in UC, and to determine if the zebrafish allows the pre-selection of therapy responsive patients.
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It is still unclear, how the in vivo trafficking of autoreactive T cells in IBD is coordinated. Preliminary data indicate that mechanical properties regulate the motility of gut T cells. Thus, we aim to investigate the interplay of intestinal T cell mechanics and trafficking in a joint effort combining the expertise of two clinician scientist PIs in cell trafficking and bioimaging. We ultimately hope to identify new targets for organ-selective IBD therapy controlling T cell dynamics in the gut.
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SNAT1 mediates the transport of neutral amino acids into the cell. Preliminary data show a significant overexpression of SNAT1 in human melanoma cells compared to melanocytes. Transient downregulation of SNAT1 resulted in significant reduction of the cellular proliferation and cell cycle progression. With this project we aim to analyze the functional importance of SNAT1, an attractive therapeutic target, in human melanoma.
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Although peritoneal metastasis correlates with poor survival in colorectal cancer (CRC), knowledge on its molecular mechanisms is rather limited. Thus, there is a crucial need for developing novel in vitro models that recapitulate peritoneal seeding and identify putative markers for therapeutic approaches. Our study aims to implement a new ex vivo mesentery model for co-culture with CRC spheroids and organoids to study gene-specific effects on tumor cell adhesion and invasion in the peritoneum.
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The aim of the proposed study is to establish a novel and reliable in vivo tumor model by engineering a breast tumor in the arteriovenous rat model. This model could provide the possibility to investigate tumor development, angiogenesis and tumor-stroma interactions in a controlled manner. Selecting appropriate scaffolds for the tumor cells is essential for the success of the model. Therefore, the study includes 3 parts to provide a structured detection of suitable matrices in vitro and in vivo.
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Non-alcoholic fatty liver disease (NAFLD) is the leading cause of hepatocellular carcinoma (HCC). Furthermore, NAFLD promotes HCC progression but the mechanism are elusive. Our preliminary work indicates that enhanced expression of prosaposin (PSAP) in NAFLD promotes HCC growth. Therefore, this project aims to characterize the molecular mechanisms by which PSAP affects HCC cells, to test the therapeutic potential of PSAP inhibition and to validate the function of PSAP in clinical HCC samples.
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Autosomal recessive mutations significantly contribute to intellectual disability and neurodevelopmental disorders (NDDs). However, high genetic heterogeneity of NDDs makes it difficult to prove pathogenicity. Using a comprehensive approach, we will combine genome sequencing and transcriptomics in a unique patient cohort of consanguineous Turkish families with at least two affected children, together with in silico analysis of candidates and in vivo screening in the Drosophila model organism.
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One third of the depressed patients do not respond adequately to conventional treatment. This seems to be associated with increased production of proinflammatory cytokines such as TNF-a and IL-1, as well as dysregulation of cortisol levels. This project aims to investigate the impact of the new psychotherapeutic method TaKeTiNa on serum lipids, cortisol Levels, and the production of proinflammatory cytokines.
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Recently, we identified atypical, antiviral IgG4 responses after immunizations with a SARS-CoV-2 mRNA vaccine. Since IgG4 responses are considered as anti-infammatory and rather tolerogenic, the impact of this type of antibody response on preventing viral infections or disease will be elucidated. Whether antigen re-exposures in form of infections or boost immunization will further shift the SARS-CoV-2 response towards IgG4 will be analysed as well as potential underlying mechanisms.
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Drug therapy in children and adolescents is often associated with uncertainties. Causes and characteristics of adverse drug reactions and medication errors are poorly understood. The main objective of the project is to establish and descriptively describe a data set with medication data and systematically collected drug-related hospital admissions of children in Germany.
Pathogenic variants in SPAST, which encodes spastin, a microtubule-severing enzyme, are the most common cause of Hereditary spastic paraplegia, a motor neuron disorder affecting the axons of corticospinal motor neurons. To date, therapeutic strategies focus on ameliorating the symptoms without treating the underlying cause. Here we investigate the effects of microtubule modifying drugs on SPAST induced pluripotent stem cell derived neurons.
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CD19-directed chimeric antigen receptor (CAR) T-cells have shown high efficacy in the treatment of B-cell malignancies and are now emerging as a standard approach for patients with relapsed and refractory disease. Despite this progress, a significant portion of patients still experience resistance to treatment. We aim to understand the intrinsic mechanisms controlling persistence and effector functions of CAR T-cells and therefore identify strategies to overcome treatment failure.
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Autoreactive T cells are thought to play a key role during the pathogenesis of rheumatoid arthritis (RA), but their specificity and their contribution to RA remain elusive. In this project, we will identify autoreactive T cells, their receptors and cognate antigens in RA patients, and study the dynamics of the autoreactive T cell response at different stages of RA. This will yield important information on the pathogenesis of RA and provide the base for a novel generation of immunotherapies.
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The transcription factor family AP2 has important functions in development. AP2e was discovered in cooperation with this PI. We newly observed delayed onset of tumorigenesis in a murine Ap2e-deficient melanoma model. This is supported by expression data showing induced AP2e mRNA expression in early tumor development and a correlation of high Ap2e expression with reduced overall survival. In the project, the role of Ap2e in development and progression of melanoma is explored in molecular detail.
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The neuropeptide Y (NPY) system was shown by the applicant to be a major driver of HCC. Transcriptome screening revealed that DEAD-box RNA helicase DDX46 is a novel and attractive NPY-regulated target in HCC. The major aims of this study are to characterize NPY-mediated regulation of DDX46 and to decipher the role of DDX46 as a novel and promising diagnostic and therapeutic target in HCC.
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Increasing survival of young cancer patients require fertility-preservation like ovarian-cryopreservation pretherapeutically with retransplantation post-therapy. However, this is not appropriate for all patients due to the risk of relapse. A promising alternative is the artificial ovary: follicles are separated from malignant cells. In the research proposed follicle survival, maturation and growth in 3D-scaffold will be observed by live cell imaging with confocal spinning disc microscopy.
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Mutations in transcriptional corepressor CtBP1 cause the neurodevelopmental disorder HADDTS. Functional CtBP1 studies in the central nervous system so far focused on neurons. We recently found that CtBP1 is also important in oligodendrocytes. Here we will characterize the oligodendroglial functions of CtBP1 and the underlying cellular and molecular mechanisms in mice and a human ES cell-derived cellular disease model to show that defects in oligodendrogenesis and myelination contribute to HADDTS
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We will analyse two new players of the rod pathway in the mammalian retina that are associated with night blindness - GPR179 and LRRTM4. GPR179 and LRRTM4 bind directly to GABAc receptors (GABAcR). Rod bipolar cells express high levels of GABAcR and deletion of LRRTM4 perturbed clustering of GABAcR at their axon terminals. We will analyse these protein complexes in the retina, map binding sites and elucidate functions of the interactions by cell biology, calcium imaging and electrophysiology.
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Reactivation of latent Cytomegalovirus (CMV) infections represent a severe, life-threatening intestinal complication in immunocompromised patients. Underlying cellular and molecular mechanisms regulating the immune epithelial cell interaction are only partially understood and targeted treatment options are not available. We seek to decipher the immune / epithelial cell interaction in the context of CMV infection combining novel ex vivo organoid co-culture with innovative genetic model systems
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T cells migrate to and impact the central nervous system (CNS) during disease. We show that diseased CNS allows stronger T cell migration by yet unknown mechanisms. Here, T cell-attracting mechanisms of neurodegenerative CNS tissue and T cell-driven neurodegenerative pathomechanisms will be investigated in a human stem cell-based 3D CNS model using RNA sequencing and biochemical methods. Data will provide mechanistic insights how T cell migration is facilitated by CNS during neurodegeneration.
2-O-Methylation of mRNA by cellular methyltransferases (MTases) enables discrimination of self and non-self. We found that SARS-CoV-2 lacking the viral MTase Nsp16 triggers an enhanced innate immune response that depends on the RNA receptor MDA5. Thus, we will analyse Nsp16 as a means of SARS-CoV-2 to counteract innate immune sensing and will test the hypothesis that the 2-O-methylation of viral RNA in general protects from sensing by the pattern recognition receptor MDA5.
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The proposed projects aims at using methods from AI-based image analysis to evaluate histopathologic samples from the field of gastrointestinal pathology. Specifically, samples from patients with inflammatory bowel diseases and malignancies of the colorectum will be evaluated. It is the aim of the project to develop algorithms that quantify and detect specific morphologic properties of these samples and integrate them with other data modalities.
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Congenital urorectal malformations are rare birth defects with serious consequences for those affected. Still, the genetic causes of which have been little researched to date. The aim of this study is to identify candidate genes for these malformations by exome sequencing and copy number analysis, to re-sequence them by next generation sequencing in a cohort of about 1100 patients and to characterise them in the zebrafish model by Morpholino oligonucleotide knockdown and CRISPR/Cas9 knockout.
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The presence of tumor-resident memory T cells (TRM) positively correlates with prognosis in many cancers. In our preliminary data, lung TRM induced by a mucosal vaccine efficiently protected against lung metastasis in a preclinical breast cancer model. We want to investigate the vaccine efficacy against lung metastases at different disease stages and the contribution of TRM and their unique features to this efficacy. The efficacy will also be assessed in combination with radio- and chemotherapy.
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With the rapid translation of emerging material processing technologies for tooth restoration, there is an urgent need for reliable laboratory testing systems that accurately predict the clinical longevity of new materials. The current proposal aims to 1) develop a novel in-vitro wear testing model that demonstrates accurate preclinical predictability of longitudinal clinical trial data and 2) explore the suitability of modern 3D-printing processes for dental material application.
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Abscopal effects are rare events of local radiotherapy (RT) inducing systemic anti-tumor immune responses leading to the reduction of tumor masses outside of the irradiation field. We hypothesize that the addition of adjuvants to high hydrostatic pressure generated whole tumor cell vaccines in combination with RT and immune checkpoint inhibition induce abscopal effects in an orthotopic breast cancer model. Further, we hypothesize that cDC1s play a central role in this immune response.
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A strict cell death regulation is indispensable for the maintenance of intestinal homeostasis, since increased cell death is able to trigger intestinal inflammation. Our newly planned experiments can help to discover the impact of the gluthathione peroxidase GPX4 on the regulation of ferroptotic cell death, as well as the induction and maintenance of intestinal inflammation. GPX4 might display a potential target for new therapeutic strategies.
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Btn2a2 inhibits T cell activation in vitro and Btn2a2-/- mice show exacerbated experimental autoimmune encephalomyelitis, suggesting a T cell inhibitory role. Strikingly, Btn2a2-/- mice exhibit elevated autoantibody titers, suggesting a defect in tolerance mechanisms. We hypothesize that Btn2a2 affects thymocytes during thymocyte selection, resulting in an altered autoaggressive T cell repertoire.
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Spondylarthritis can lead to stiffness of the spine and consequently to impaired function. Therefore, it is important to promote daily exercises in Spondylarthritis (SpA) patients. The objective of this study is to assess the feasibility of Yoga to affect spine mobility and disease activity in SpA patients. By measuring the mobility and improving spine flexibility, patients feel better with their disease and learn how important daily exercising is.
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Reactive carbonyl species (RCS) are linked to development of metabolic syndrome including neuropathic pain and steatotic liver disease (MASLD), but the possibly synergistic role of RCS in both conditions remains to be investigated. This project aims at analyzing RCS as biomarkers in patients with neuropathy and neuropathic pain, with parallel compre¬hensive experimental neurophysiological examinations of pa¬tients and assessment of functional effects of RCS on sensory neurons in vitro.
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Serotonergic psychedelics represent a potential breakthrough in therapy of several neuropsychiatric disorders. Here we focus on the molecular mechanisms underlying their action on neuronal level, specifically aiming to elucidate their effects on presynaptic function that governs neurotransmitter release, and how these relate to neuronal activity and neuroplasticity. Our results will provide important mechanistic insight into the action of these putative rapid-acting antidepressants.
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The aim of the intended research project is to investigate the role of the transcription factor AhR in B-cells in the establishment of an antigen-specific humoral immune response. Therefore, B cell-specific AhR-deficient mice and control animals will be 1. immunized in a T-cell-dependent manner while fed a diet containing AhR ligands and 2. their B cells will be activated in vitro and analyzed in detail. In addition, AhR target genes in B cells will be determined (RNASeq)
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A computer based body exposure to reduce body dissatisfaction in adolescents suffering from Anorexia nervosa (AN) will be evaluated. Within an RCT, intervention effects will be compared to treatment-as-usual; furthermore, AN-specific characteristics should be identified in a comparison with a highly body-dissatisfied control group. In a multi-level approach, potentially underlying mechanisms in terms of the subjective and objective stress reactivity as well as gaze patterns will be analyzed.
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The standard of care treatment for HER2-positive breast cancer patients includes an anti-HER2-targeted antibody treatment. The antibody dependent cellular cytotoxicity (ADCC) is a key player associated with treatment response. Thus, the aim of the presented project is to conduct an ADCC biomarker assay in order to evaluate the association of ADCC capacity of peripheral blood mononuclear cells (PBMCs) with therapy response after neoadjuvant treatment with the trastuzumab-biosimilar ontruzant.
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Systemic Sclerosis (SSc) is a fibrosing disorder with a high lethality. We demonstrate that Hedgehog-Signaling and AP1-signals mutually amplify in fibrosing disorders. We plan to analyze the effects of the combined inhibition of both signaling pathways on the evolvement of fibrosis and the mechanisms of mutual amplification. We will investigate the association of combined upregulation of both pathways with clinical patient data and investigate potential prognostic implications.
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Regulatory macrophages are crucial to induce resolution of inflammation. Excessive macrophage activation is associated with transplant rejection or chronic of inflammatory diseases. Our preliminary murine data revealed that sCD83 induces regulatory macrophages , whilst mCD83 deletion drives macrophages towards a pro-inflammatory phenotype. This project aims to translate these interesting findings into the human macrophages system.
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In this project we want to investigate cell-to-communication via exosomes and functionalized nanoparticles in the context of glomerular diseases.Therefore, we will characterize microvesicles secreted from glomerular cells regarding size and surface markers with electron and fluorescence microscopy and flow cytometry. Also, we want to study functionalized nanoparticles in vitro in glomerular cells and in vivo in a zebrafish model. Lastly, we want to establish an autophagy model in zebrafish.
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Defect reconstruction in plastic surgery using tissue transfer, so called flaps, is a standard procedure, for example after Tumor resection. The proposed study evaluates the effect of topically stem cell or growth factor application on the size of the necrotic area of irradiated and post-ischemic random pattern flaps in an in-vivo model.
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Changes in (T cell receptor) TCR repertoire can directly impact on the breath and magnitude of antigen-specific T cell responses. During treated HIV infection, dysfunctional T cell responses associate with inflammation that is at least in part driven by microbial translocation. Therefore, we aim to investigate the relationship between the translocated microbiome, the TCR repertoire and T cell functionality, with emphasis on vaccine-induced antigen-specific responses.
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Vulvar cancer is a rare gynecologic tumor with increasing incidence. New therapeutic strategies include the use of checkpointinhibitors, but clinical data is limited and contradictory. In this project we aim to assess the expression of PD-L1 in vulvar cancer. The expression will be assessed independently in primary, recurrent and lymph node metastasis. The expression will be compared to the clinical status such as TNM, L-,V-,Pn-infiltration.
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Epidemiological studies showed that alcohol intake reduces the incidence of RA. We published that alcohol sourced acetate prevents Tfh:B cell conjugates, crucial for antibody secretion. Here, we provide data showing that acetylation of cytoskeletal proteins by acetate reduces T cell motility. We propose to study if increased acetate levels favor cytoskeletal protein acetylation impacting cell motility and migration with direct consequences on the onset of autoimmunity and vaccination efficacies.
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Aberrant activation of bone resorbing osteoclasts causes osteoporosis. We found that the b-blocker metoprolol inhibits osteoclast development and resorption activity and increases bone mass in mice. In this project, we aim to investigate the mechanisms how metoprolol inhibits osteoclasts, focusing on its dependency on b-adrenergic receptor signaling and its effects on osteoclast fusion, motility and resorption. The long-term goal is to find new treatment strategies against osteoporosis.
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Phosphorylation is a well-known regulatory mechanism of MTOC activity at the centrosome. In contrast, it is unknown, whether non-centrosomal MTOCs are also regulated by phosphorylation. We aim at determining how phosphorylation is utilized to regulate MTOC formation at the nuclear envelope. For this, we will examine a potential role of candidate enzymes derived from preliminary data as well as utilize screening approaches to identify novel regulators of nuclear envelope MTOC formation.
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Learning and memory formation are influenced in a sex-specific manner by neurosteroids, such as 17beta-estradiol and dehydrotestosterone. However, the structural mechanisms of how de novo synthesis of local neurosteroids in hippocampal neurons and their regulation by gonadotropin releasing hormone (GnRH) lead to the formation and degradation of spine synapses are still poorly understood. The focus of this work is to investigate its influence on calcium homeostasis in both sexes.
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The transcription factor NFATc3 is important for regulating T cells. Patients with inflammatory bowel disease had high numbers of NFATc3+ cells in the lamina propria indicating an involvement of NFATc3 in mucosal inflammation. To investigate NFATc3 and colitis we will use specific knockout mice in experimental colitis models and analyse its molecular function. The results should clarify the role of NFATc3 in intestinal inflammation and provide a basis for NFATc3 as a new therapeutic concept.
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The VATER/VACTERL association describes the co-occurrence of malformations of the vertebral bodies, anorectum, heart, esophagus, kidneys, and limbs. The proposed study aims to identify new candidate genes and characterize the candidate gene FZD7 by morpholino knockdown and expression analysis in developing zebrafish larvae. In doing so, we hope to better understand the molecular mechanisms leading to this multisystem malformation.
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Chemical Exchange Saturation Transfer (CEST) MRI at 7T can provide high-quality metabolic maps for research in knee osteoarthritis, with a potential to replace the biopsy. Heterogeneity of the main magnetic field and constraints of the Specific Absorption Rate (SAR) make the fat suppression and the metabolite quantification challenging. This project aims to implement a routine for dynamic fat suppression pulse calculation including fields inhomogeneities and SAR limits specific to the subject.
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The metabolism of reconstituting NK cells upon autologous SCT is altered in lymphoma patients who experience an early relapse upon transplantation. We intend to decipher the underlying cellular and molecular mechanism to identify factors leading to the increased relapse risk and to reveal potential opportunities to modify them. This will lay the foundation for further projects investigating NK cell reconstitution upon allogeneic SCT and CAR-transfected NK cell expansion in tumor patients.
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A healthy skeleton relies on a balance between bone-forming osteoblasts and bone-resorbing osteoclasts. A shift towards increased osteoclast activity can therefore lead to bone loss. The immune system strongly affects osteoclast biology, usually promoting osteoclast development. Interestingly, we demonstrated that eosinophils negatively regulate osteoclast formation and activity. Thus, it is of high relevance to unveil the molecular mechanisms underlying this regulatory function of eosinophils.
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SSc is the systemic rheumatic disease with the highest disease-related mortality. We identified DAX-1 as a mediator of fibroblast activation. We showed that DAX-1 is upregulated in fibrotic skin and that knockdown of Dax-1 ameliorates skin fibrosis. We plan to further characterize the mechanism of DAX-1 upregulation and study its potential transcriptional role in fibroblast activation as well as its potential antifibrotic role in 3D skin models and precision cut tissue slices from SSc skin.
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Proper Schwann cell development and myelination are essential for a functional peripheral nervous system and regulated by networks of chromatin modifiers and transcription factors. Here I plan to study the role of the acetyltransferase Tip60 as part of the Tip60/Ep400 chromatin remodeling complex in lineage progression and myelination by characterizing its target genes and interaction with transcription factor Sox10. Results may help to better understand peripheral neuropathies.
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Alcoholism and depression are highly comorbid disorders. Neutral sphingomyelinase (NSM) is suggested as a missing link between emotional status and alcohol consumption due to the downstream effects on the serotoninergic system. A new line of mice with NSM gene knockout specifically in the brain serotoninergic system was created to investigate if the interaction between NSM and the brain serotoninergic system determines the comorbidity between negative emotional state and alcohol consumption.
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Glucocorticoids are amongst the most important anti-inflammatory drugs, promoting inflammatory resolution via the functional reprogramming of macrophages, a process that promotes itaconate production. Though itaconate is a metabolite participating in immune-metabolic rewiring, its role and effects, as with the underlying mechanisms involved in its production, on immunometabolism and inflammatory resolution remain unknown, yet could contribute to further optimizing glucocorticoid treatment.
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Inflammatory bowel disease (IBD) predisposes for synucleinopathies like Parkinson Disease. This is putatively caused by propagation of chronic inflammation into the brain. The hypothesis of this project is that chronic inflammation in IBD activates microglia in distinct brain regions, thereby mediating neuronal pathology and aggravating synucleinopathy. This hypothesis will be tested in post mortem brain tissue of IBD patients and mice with colitis.
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Trauma is the leading cause of death in humans aged below 45. Trauma can affect everyone, everywhere at any time. Blunt cardiac injury is associated with increased mortality after trauma. Redistribution of the gap junction protein Connexin43 is associated with cardiac dysfunction. In the present project, important new molecular insights into the regulation of Cx43 in the heart after trauma will be revealed and may identify therapeutic targets for preservation of cellular coupling.
In patients with periodontitis, orofacial clefts and partly also during orthodontic treatment an oral dysbiosis and an increase of inflammation markers have been observed. Here, for the first time a systematic analysis of the oral microbiome and local inflammation in oral niches will be carried out using 16S rDNA sequencing and multiplex immuno assay, which will be correlated with determinants such as gingivitis/periodontitis, age, orofacial clefts, exogeneous factors and orthodontic treatment.
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The ?-secretases (Bace1 and Bace2) are proteases involved in the pathogenesis of Alzheimers disease (AD). However, Bace1/2 can be found in tissues other than the brain, suggesting that their role goes well beyond AD. Interestingly, our preliminary data reveal that the expression of Bace1/2 is modulated in response to intestinal inflammation and during cancer development. We hypothesize that the ?-secretases might have regulatory functions in the gut and the pathophysiology of colorectal cancer
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In this project, the role of GPR15L in the formation and development of colorectal carcinoma will be investigated. For GPR15L anti-proliferative effects on tumor cell growth have already been shown in vitro and our aim is to also confirm these effects in a mouse model in vivo. In addition, we want to investigate the influence of GPR15L on the intestinal microbiome in relation to the development and progression of colorectal carcinoma in vitro and in vivo.
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Basic research focusing on TCs differentiation might contribute to the understanding of pleiotropic immune functions of the intestinal epithelium, which can be exploited in the context of immunomodulation. Our preliminary data support an interplay between type2 cytokines and Rac1/RhoA function within IECs playing a role in the differentiation of IECs towards a TCs fate. Our aim is then to decipher the molecular mechanisms operating behind intrinsic/extrinsic control of TCs cell fate decision.
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SiFAr-Stress investigates the impact of cycling on stress level in older adults. Uncertainty due to change to motorized bicycle or fear of falling can be perceived as stressors for cyclists. Stress activates different physiological signal cascades and stimulate for their part low-grade inflammation, which in the long-term can be associated with negative health outcomes. The aim is to analyse inflammatory processes as well as the activity of stress systems.
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We aim at generating multicellular engineered tissues based on hiPSC-derived endothelial cells and cardiomyocytes in a collagen-based hydrogel mimicking the fibrous structure of the native cardiac matrix. We will determine whether such hydrogels provide a proper environment to enhance pre-vascularization utilizing hiPSC-derived endothelial cells and whether cardiomyocyte maturation as well as pre-vascularization is enhanced in 3D engineered multicellular cardiac tissues.
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Severe dissociative disorders are characterized by distinct self-perception-related stress accompanied by autonomic blunting. The aim of the current study is to investigate self-reported, psychophysiological and biological stress reactions upon an experimental self-perception paradigm in patients suffering from diverse post-traumatic conditions with different levels of dissociation, to elucidate potential associations between dissociation intensity and the aversiveness of self-perception.
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Inflammatory bowel diseases (IBD) include two major subtypes: Crohns disease (CD) and ulcerative colitis (UC) with immunological dysfunction underlying its development. Changes in the oral mucosa and changes in the periodontium can also be observed. Periodontitis (P) is defined as a dysbiotic inflammatory disease, however, the relationship between the incidence and severity of periodontitis and cytokine expression in IBD patients remains unclear.
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T cells are an integral part of adaptive immunity, which forms the basis of protection from infections after vaccination. While B cell and antibody responses are well understood, little is known about which antigen-reactive T cells are recruited after primary and booster vaccination, as well as into long-lasting resting memory. In this project, we will investigate these questions in SARS-CoV-2 vaccinees by state-of-the-art T cell receptor repertoire profiling and functionality assessments.
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Multiple system atrophy (MSA) is characterized by neurodegeneration and neuroinflammatory response of myeloid cells. The goal of this project is to decipher the role of microglia in disease mechanisms of MSA. Depletion of microglia results in improved survival, however, also in behavioural motor deficits in a MSA mouse model. Structural, biochemical and transcriptional approaches will be used to characterize changes in neuronal connectivity and synaptic networks upon microglia depletion in MSA.
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Both host environmental components as well as host cells release Extracellular vesicles (EVs) who are increasingly recognized for their immune-stimulatory properties and their potential role as biological shuttle system for inter-kingdom communication. Within this project, we will elucidate the role of extracellular vesicles as communication system and the impact of such vesicles on the pathogenesis of immune-mediated inflammatory diseases.
This IZKF grant will be essential to realize my vision of using direct lineage reprogramming for the identification of novel regulators of human neurogenesis. My data provide evidence for the exciting opportunity to identify new potential molecular targets to enhance and navigate human neurogenesis for improving reprogramming and understanding developmental neurogenesis. We will study putative new neurogenesis key players during direct lineage reprogramming and early human brain development.
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Osteoclasts are the bone-resorbing cells of the body, which lead to severe damage of the musculoskeletal system under pathological conditions (such as RA). Treatment with soluble CD83 inhibited bone destruction in the murine arthritis model. Aim of this proposal is the translation of the murine data into the human system, which repre-sents the next important step towards future therapeutic applications.
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We found immunotoxins - fusion proteins of toxins and antibodies - synergistically enhanced 100-fold by Paclitaxel. We developed Duotoxins combining Paclitaxel-like DM1 and immunotoxins on one antibody. But, conventional immunotoxins cannot be conjugated efficiently. After switching to full-length antibodies, an active Duotoxin was generated. Here, we aim to use novel technology to extend the concept to other targets before applying for an extension of current DFG grant.
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Functional organisation of brain circuits supporting adaptive behaviours has informed development of novel therapeutic interventions. In this interdisciplinary proposal we will combine artificial intelligence approaches with innovative electrophysiological recordings in behaving mice to decipher neural representations of innate behaviours in the hypothalamus. The results will enable new insights into the function of a blueprint circuit for behavioural command.
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Diagnosis of the rare neurodegenerative disease multisystem atrophy (MSA) is hampered by a lack of biomarkers. We could show that in an MSA mouse model, a myelin deficit can be visualized by quant. susceptibility mapping (QSM)on MRI. Our preliminary clinical data show similar results. The aim is now to comprehensively assess QSM imaging as a biomarker for the differential diagnosis of neurodegenerative diseases.
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Intestinal barrier integrity is an important checkpoint in translating autoimmunity to inflammation in rheumatoid arthritis (RA). Microbial metabolites of tryptophan were shown to reduce intestinal permeability and inflammation. However, it is unknown if this translates to a favourable impact on RA. Furthermore, it is unknown how the metabolites are intestinally resorbed. These questions should be adressed in cell models of intestinal epithelium and in human serum samples.
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The scientific aim of this work is to further develop the metabolic chemical exchange saturation transer MR fingerprinting (CEST MRF) and to translate it from previous animal experiments to human MRI scanners at 3T and 7T. This will enable accelerated quantitative CEST imaging that forms a metabolic MR fingerprinting approach, which can then be evaluated for its potential clinical benefit for tumor diagnosis and stroke prognosis at University Clinic Erlangen.
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Pericytes are small cells around brain capillaries and play a major role in maintenance of the blood brain barrier. In intracerebral hemorrhage (ICH), blood products induce complex processes leading to dysfunction of pericytes, impairment of the blood brain barrier and perihemorrhagic edema (PHE) formation. Aim of this study is to identify the blood metabolites triggering pericyte dysfunction to develop treatment strategies against PHE formation and to improve functional outcome of ICH patients.
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Cluster of Differentiation 109 (CD109) is a cell surface protein that is GPI anchored in the cell membrane. It belongs to the ?2-macroglobulin, C3, C4, C5 protein family and is expressed on keratinocytes, platelets, immune stem cells as well as CD4 and CD8 positive T-cells. In recent years CD109 was also described as risk factor for several tumour entities. In this project we will elucidate the interactome of CD109 on the cell surface and evaluate resulting cell- type specific changes.
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I investigate rare glomerular diseases with different cell culture models, transgenic zebrafish models, podocyte specific knockout models, innovative techniques, interdisciplinary collaborations and patient material to cover multidimensional aspects of the disease in a patient centered manner. Cell-cell signaling through miRs, exosomes, autophagy and circulating factors are investigated to learn more about pathomechanisms of rare glomerular diseases that might translate into novel therapeutic targets…
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Aim of the proposed study is the definition of an independent parameter for the diagnostic evaluation of the perfusion situation of the calf muscle based on MSOT-method in a cross-sectional collective of healthy volunteers and patients with different stages of PAVK (study group 1). The validation of the results will be performed by an independent validation group (study group 2).
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Recent studies suggest that glial dysfunction significantly contributes to neurodegeneration in Parkinsons disease (PD). Since lysosomal degradation is important for glial cell function, we aim to analyse the molecular consequences of lysosomal dysfunction within different glial cell lines. A better understanding of glial regulation and lysosomal turnover will help to unravel molecular mechanisms in PD and might facilitate the identification of novel therapeutic strategies in PD.
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Lung cancer is the most prevalent and deadly type of cancer. Although immunotherapy with checkpoint inhibitors can improve the clinical outcome, only a minority of patients responds to this treatment. Recent studies suggest that tissue-resident memory T cells (TRM) in the tumour mass correlate positively with prognosis and are essential for efficacy of immunotherapy. In the present study, a novel mucosal vaccination strategy will be employed to induce lung TRM against defined tumour antigens.
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I could previously identify resident tissue macrophages (RTM) as anti-inflammatory protectors of stromal integrity. The molecular mechanisms that regulate this tissue-protective function, however, are unknown. My preliminary work strongly suggests that within stromal tissues exist extensive, heterocellular communication networks. I hypothesize that functional network communication between stromal fibroblasts and RTM coordinate biological behavior of tissues and facilitate RTM functionality.
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During development a small starting population of neural stem cells (NSCs) give rise to all neurons and macroglia cells in the mature central nervous system. Hence, controlling NSC decisions is crucial for the accurate production of the right amount of the desired cell types at the right time and place. Here we aim at determining cellular features that allow a prospective identification of lineage choices and thus will facilitate to reveal the molecular logic of decision-taking processes.
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Fibrotic diseases account for 45% of the deaths in the developed world. We demonstrate that the nuclear receptor TR4 is overexpressed in fibrotic tissues in a TGFbeta-dependent manner. TR4 promotes fibroblast-to-myofibroblast transition and collagen release. Knockout of TR4 prevents fibroblast activation and ameliorates experimental fibrosis. In the proposed project, we aim to characterize the molecular mechanisms of fibroblast activation by TR4 and the antifibrotic effects of TR4 inhibition.
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Intestinal strictures are a major disease burden in Crohns disease. Conventional cross-sectional imaging modalities are currently not able to differentiate between inflammatory and fibrotic components of strictures. This would be essential for the initiation of the appropriate therapy. In a translational approach we want to investigate whether optoacoustic imaging can be used to quantify hemoglobin as a sign of inflammation and collagen as a sign of fibrosis in murine and human intestine.
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We aim to investigate the composition of the gut virome as a marker for resistance against anti-TNF therapy in Crohn's disease patients. We will functionally characterize the interaction of identified viruses with mucosal CD14+ macrophages. In particular, we will analyze mechanisms of increased mucosal IL23R expression and IL-23 production that mediate molecular resistance to anti-TNF therapy in Crohn's disease, to finally elucidate a signaling pathway that determine non-response to therapy.
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To understand the role played by ubiquitination of type I interferon in the pathogenesis of inflammatory bowel disease we intend to induce DSS colitis in two newly generated conditional mouse strains i.e. Stat2 and Smurf2 in experimental colitis models. CRISPR/Cas, three dimensional organoids coupled with Nanostring and RNA-Seq/GO analysis will be used to understand molecular mechanisms underlying DSS findings. Data will be validated using samples from IBD patients and controls.
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While the influence of T cells on bone homeostasis has been well characterized, less is known about the role of B cells. Despite that B cells are able to produce RANKL, the major cytokine regulating osteoclast differentiation, its regulation of expression remains unclear. B cells reside in the low oxygen concentrations bone niche, and adapt to the environment through the expression of HIFs. I therefore hypothesize that HIF expression in B cells could influence the development of osteoporosis.
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DNA damage repair deficiency is common in triple-negative breast cancer, especially in the presence of BRCA1/2 mutations, and is associated with a higher mutational load and immunogenicity. In this project, multi-spectral imaging will be used to investigate the spatial distribution of different immune cells in specimens of triple-negative tumors from 40 patients (BRCA1+, BRCA2+, WT) and their influence on clinical parameters.
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Intestinal fibrosis is a common complication in IBD and has limited therapeutic options. IL36R ligands are upregulated in CD and UC patients as well as CD patients with stenosis. The systemic blockade of IL36R signaling reduces intestinal inflammation and fibrosis in vivo. Deciphering the cell-type-specific roles of IL36 via the newly generated IL36Rfl/f mouse strain will help to understand the mode of action of a neutralizing IL36R antibody in humans.
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This application by a medical historian seeks initial funding to compile the historical sources nessesary to study the perception of the ancient hippocratic treatise On the Sacred Disease by scholars and physicians of the 19th and 20th century, nowadays regarded as one of the most iconic ancient texts defining the rational core of the Western medical tradition. If the research question proves feasible, a DFG project proposal will follow.
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Ferroptosis is a novel form of regulated cell death with major importance in inflammatory conditions. The proposed study will elucidate the functional role of ferroptosis and its main regulator GPX4 in the lung under steady-state conditions and in the pathophysiology of the inflammatory lung disease of bronchial asthma. By characterizing the molecular pathways involved, we aim to lay the foundation for the development of new therapeutic avenues in the treatment of this frequent disease.
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As lymphatics in the inflamed joint in rheumatoid Arthritis drain specifically the popliteal lymph node (pLN) where the adaptive immune response is initiated, we investigated a population of stromal cells in the pLN, namely the fibroblastic reticular cells (FRC). Our preliminary data show a significant immunomodulatory potential of pLN FRCs in inflammatory arthritis mouse models. Therefore, we hypothesize that specifically pLN stromal FRCs play a so far neglected role in the early onset of RA.
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Molecular ultrasound of inflammatory bowel disease has not yet been established. We want to exploit the essential role of endothelial cell adhesion molecules in the development of colitis and establish CAM (cell adhesion molecule)-specific ultrasound contrast agents in DSS-induced murine colitis for the analysis of colonic inflammation. This will facilitate both, assessment of disease progression and treatment response monitoring.
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Clinical and animal studies implicate neuroinflammatory features (interleukines, chemokines, adipokines, oxytocin, alarmins) as part of the pathophysiology. BurstDR-SCS and DRG-SCS stimulation present a paradigm shift in current neurostimulation to address the treatment of CPSP-associated pain. Such molecular analysis may underpin the emerging role of CPSP-related molecular patterns as potential biomarkers to reliably reproduce spinal stimulation effects.
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Orofacial clefts are frequent congenital malformations. Etiology is complex, poorly understood and involves environmental and genetic factors. We could identify several cranial neural crest transcription factors and chromatin remodelers as key regulators of palatal development. We now use genome-edited cell lines and mouse mutants to determine the exact function and relationship of these factors in their regulatory network and thus better understand palatal development and orofacial clefting.
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Recent data indicates that adult neural stem cell dysfunction and the resulting impairment of adult hippocampal neurogenesis contributes to cognitive deficits in human ageing and neurodegenerative diseases. The mechanisms underlying ageing-associated neural stem cell dysfunction are largely unknown. This project will investigate the hypothesis that dysfunction of lysosome-dependent degradation pathways is a major contributor for hippocampal neural stem cell dysfunction during ageing.
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The renal cancer risk SNP on chromosome 14q24.2 creates a novel Hypoxia inducible transcription factor (HIF)-binding DNA element in an intronic region of the DPF3 gene, a member of the SWI/SNF chromatin remodelling complex. DPF3 is upregulated in a SNP- and HIF-dependent fashion in renal tubular cells. We investigate the regulation of DPF3 in renal cells and cancer as well as its contribution to global chromatin status and transcription factor binding to critical DNA regions.
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Dendritic Cells (DCs) are indispensable for the protection from pathogens. Additionally, natural antibodies (nAbs) reacting to evolutionary conserved epitopes foster fast targeted response. Leishmaniasis is an important tropical disease with different manifestations. However, the first events in infection and determination of T/NK cell responses by DCs and nAbs are not fully understood. We now aim to unravel early determining factors for clinical outcome in leishmaniasis on a single cell level.
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Despite the improvement through tyrosine kinase inhibitors (TKIs), treatment resistance, relapse and therapy-induced side effects are central problems of CML therapy. Our interdisciplinary project addresses the question whether and how TKIs alter CML cell metabolism and induce synthetic lethality in combination with compounds specifically targeting metabolic pathways. Our approach could help to improve efficacy and reduce side effects of CML treatment in pediatric and adult patients alike.
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Inflammation within the CNS can directly affect neuronal structures. Thus, molecules controlling inflammatory responses are of upmost importance. The immune-regulatory CD83 molecule is highly expressed by microglia and tissue-resident macrophages and thus, represents a crucial factor for microglial activation and the neuro-immune crosstalk. Since, its regulation and function in these cells has not been elucidated we will investigate this during immune homeostasis and neuroinflammation.
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Systemic sclerosis (SSc) is a prototypic fibrotic disease, with TGF-beta as a key mediator of fibroblast activation. Engrailed-1 (EN1) identifies a fibroblast lineage with intrinsic fibrogenic potential. We showed that EN1 was upregulated in fibrotic skin by TGF-beta, and that EN1 knockout partially prevented fibroblast activation and fibrosis. Next, we aim to study EN2 in fibrosis, to evaluate how EN1 is upregulated and to provide further evidence for the role of EN1 in fibroblast activation.
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In search for better glomerular ex vivo models, we studied 3D glomerular co-cultures and generated stem cell (iPSC)-derived personalized podocytes from patients with genetic FSGS. These cells were characterized using bulk sequencing, marker expression, actin polymerization, morphology and response to different substances used in the clinic to foresee individual response to treatment. At the moment, CRISPR-Cas9 based rescue experiments of mutated iPSC derived patient podocytes are performed.
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Our preliminary data identified a unique Cx3Cr1-positive macrophage subset that forms a protective barrier around the joint and counteracts inflammation. Accordingly, we will address the developmental origin and differentiation pathways of these specific macrophages and try to understand the molecular basis of their anti-inflammatory properties. Moreover, we will address the relevance of these findings for human diseases such as rheumatoid arthritis.
SAPHO syndrome is a rare inflammatory disease of the skeleton and skin with unsolved etiology, but suspected causal/ disease-contributing genetic factor(s). We identified several rare PLXNA1 variants in patients with SAPHO syndrome. We propose to identify the molecular mechanisms by those human variants that lead to disease. Our study will allow to understand the etiology of SAPHO and to pave the way for planned analyses in vertebrates and genetic follow-up studies.
We have shown that pericytes derived from the adult human brain can be reprogrammed into induced neurons (iNs) by overexpressing the transcription factors Ascl1 and Sox2. A major challenge to further assess functionality of iNs is posed by the lack of human model systems to study whether iNs adopt properties of human bona fide neurons. In the present proposal we therefore aim at assessing the impact of the cellular microenvironment provided by brain organoids on the reprogramming outcome.
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To investigate if high amounts of tumor cell dsRNA derived from ERVs regulate the tumor immune microenvironment by activating the viral alarm or IFN response leading to high anti-tumor lymphocyte infiltration including establishment of tertiary lymphoid structures as well as adaptive responses (immune checkpoints, negative regulatory immune cells and ECM production) already in early precursor stages of muscle-invasive bladder cancer and how they might evade the immunosurveillance.
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Despite the improvement through tyrosine kinase inhibitors (TKIs), treatment resistance, relapse and therapy-induced side effects are central problems of CML therapy. Our interdisciplinary project addresses the question whether and how TKIs alter CML cell metabolism and induce synthetic lethality in combination with compounds specifically targeting metabolic pathways. Our approach could help to improve efficacy and reduce side effects of CML treatment in pediatric and adult patients alike.
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We have identified PU.1 as a key regulator of fibroblast polarization. Its role in colorectal carcinoma (CRC) is unknown. We will address the following aims: (1) characterization of cancer-associated fibroblast (CAF) heterogeneity in CRC, (2) analysis of CAF polarization-dependent fibrocrine effects in vitro and (3) in experimental animal models, and (4) validation of the results in CRC tissues. Deciphering the role of fibroblast polarization in CRC may provide a new target for therapy.
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T cell mediated intestinal inflammation in acute Graft-versus-Host-Disease (GI-GvHD) represents a life-threatening and therapeutically challenging complication in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Interestingly, the role of tissue-resident memory T cells (Trm) in this context is unknown. Here, we plan studies to assess the development, migration, location and functionality of Trm cells in GI-GvHD both in murine experimental models and in men.
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Chronic kidney disease represents the fastest growing pathology worldwide. Elucidating new regulators of kidney development and disease will promote the development of strategies for kidney repair. Here we propose to identify how the adhesion G protein-coupling receptor Gpr126 regulates kidney development and which diseases are associated with altered Gpr126 expression in order to design in the future experiments to determine whether Gpr126 inhibition or activation can improve kidney function.
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A synthetic peptide inhibits Wnt/ß-catenin signalling and growth of colorectal cancer cells by augmenting conductin-mediated ß-catenin degradation. Here, we want to improve peptide activity by optimising its functional and its cell permeability-providing parts. Then, cell penetration kinetics, cellular distribution and stability will be characterised, and the optimised peptide will be functionally compared to the old version to verify improvement of our peptide towards therapeutic applicability.
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In RA the degree of inflammation and autoantibody positivity are important initiators of bone destruction. Interestingly, among IBD patients with chronic gut inflammations about 45% were positive for at least one arthritis antibody. However, despite the reported higher incidence of bone destruction in IBD patients, it remains elusive whether and how local gut antibody production and their different posttranslational modifications during gut inflammations directly contribute to RA.
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Recent data demonstrate profound immunological alterations in Parkinsons disease (PD). We study the contribution of the peripheral immune system to onset and progression in PD. Specifically, we perform a comprehensive characterization of peripheral immunity in early vs. late onset with rapid vs. slow disease progression PD patients. Subsequently, we will determine neurotoxicity in human autologous co-cultures of stem cell-derived midbrain neurons and specific immune cells.
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Recent data demonstrate profound immunological alterations in Parkinsons disease (PD). We study the contribution of the peripheral immune system to onset and progression in PD. Specifically, we perform a comprehensive characterization of peripheral immunity in early vs. late onset with rapid vs. slow disease progression PD patients. Subsequently, we will determine neurotoxicity in human autologous co-cultures of stem cell-derived midbrain neurons and specific immune cells.
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Liver biology and liver diseases are difficult to study using current in vitro models. We developed a new method to isolate and expand self-renewing liver organoids from the embryonic liver. Within this project we aim to understand how microbiome-associated signaling pathways influence maturation, injury and regeneration of the liver by using these organoids. Thus this project will provide new insights in the critical role of liver-gut communication and potentially hepatic disease development.
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Oncogene-induced senescence (OIS) was recently introduced as a strong tumor suppressive mechanism seen e.g. in development of nevi out of melanocytes after BRAF mutation. Tumor cells like melanoma obviously can overcome these limiting mechanisms by further changes, however the molecular mechanisms leading to and overcoming OIS are just being started to be understood. We aim to understand the role of cell adhesion processes and mechanotransduction in induction and overcoming OIS.
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The highly oncogenic retrovirus Human T-cell leukemia virus type 1 (HTLV-1) causes incurable neoplastic or inflammatory diseases. The viral accessory protein p8, which is proteolytically cleaved from the precursor p12 and transported to target cells prior to infection, is important for establishing persistent infections in vivo. Here, we aim to identify the protease cleaving p12 into p8, to inhibit this protease, and to assess the impact of blocking of p12/p8 processing on viral persistence.
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This proposal will focus on the molecular basis of tumor inflammation of two different advanced cancers; Bladder cancer (MIBC) and Ovarian cancer (OVCA) with poor survival outcomes and high recurrence rates. Endogenous retrovirus (ERV) activations are linked with innate immunity and tumor inflammation. We will correlate patient immune signatures with ERVs and determine the functional role of ERVs, including dsRNA and RNA/DNA intermediates using tumors, cell lines and tumoroids of MIBC and OVCA.
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Axin is a key negative regulator of the oncogenic Wnt/beta-catenin pathway scaffolding the beta-catenin destruction complex. We suggest that the newly found anchoring of axin to microtubules (MTs) is of functional importance for regulating the pathway. We will (i) describe the dynamics of axin association with MTs; (ii) determine the biochemical basis of this interaction and its regulation by phosphorylation; and (iii) define the functional role of axin anchoring to MTs in Wnt signaling.
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Rheumatoid arthritis (RA) is linked to neuropsychiatric comorbidity like depression due to inflammatory brain involvement. This project aims to investigate the influence of chronic peripheral inflammation on the blood brain-barrier and macrophages in different brain regions in an RA mouse Modell and human post mortem tissue. Thereby, local factors promoting inflammatory susceptibility or resilience may be identified as therapeutic targets for the CNS involvement in RA.
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Neuropeptide Y (NPY) and its receptors represent a highly conserved system which is involved in cancer-related hallmarks. However, the impact of the NPY-system on hepatocellular carcinoma (HCC) remains unclear. The aims of this study are i) to unravel the role of NPY-receptor/NPY-crosstalk in resistance to tyrosine kinase inhibitors such as sorafenib and lenvatinib in HCC, and ii) to analyze the unknown role of the NPY-system as a potential major determinant of immune-escape in HCC.
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Abnormal neo-ossification in humans with SpA and gout are common, but there are only few suitable animal models. Conventional methods require a high number of animals or can only insufficiently distinguish between inflammatory edematous swelling and/or increased bone thickness. The aim of this application is to establish a mouse model of gouty enthesitis in vivo by means of a non-invasive combination of MRI and PET/CT, in which live animals can longitudinally be examined.
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In about 15 % of affected patients ADPKD (autosomal dominant polycystic kidney disease) is caused by mutations in the PKD2 gene coding polycystin-2 (PC2). Altered ion channel properties of PC2 may contribute to the pathophysiology of ADPKD. This project uses a novel experimental strategy to study the electrophysiological properties of PC2 and mutant PC2 channels in combination with molecular modelling. Its aim is to improve our understanding of PC2 ion channel function in health and disease.
HCMV replication is characterized by viral CDK-cyclin interaction. The CDK-like viral kinase pUL97 interacts with human cyclins. CycB1 is phosphorylated upon the interaction, dependent on pUL97 activity, whereas cycT1/H interaction stimulates pUL97 activity and substrate phosphorylation. Regions for cyclin interaction and antiviral drug resistance show overlaps in pUL97, so that this correlation will be elucidated in terms of viral fitness for the development of a novel antiviral strategy.
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We have discovered Gasdermin C as a protein strongly induced in the gut epithelium by IL-4 and IL-13. We can show that Gasdermin C is released by goblet cells into the mucous layer where it binds to bacteria. Further analyses implicate that Gasdermin C has a pore forming function and promotes anti-microbial defence. We plan to elucidate the regulation of Gasdermin C, its molecular mode of action and its functional impact in vivo.
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We identified RANTES as a key regulator of the resolution of allergic asthma in human and murine studies. Resolved symptomatic episodes of asthma in children, were found to be associated with elevated serum levels of RANTES indicating the involvement of RANTES in the resolution of allergic asthma. In a murine model after allergen (HDM) challenge, RANTES cured allergic asthma trait. In this project, we want to better understand the mechanism of RANTES mediated resolution of allergic asthma.
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Tissue-resident macrophages (tirM?) contribute to steady state physiology in tissues but also modulate and terminate inflammatory processes. Gene expression data revealed that CD83, a molecule with potent immunoregulatory properties, is highly expressed in tirM?. However, the biological relevance of CD83 expression by macrophages is poorly understood. Thus, this project aims to elucidate the role and regulation of CD83 in tirM? and in macrophages under pro- and anti-inflammatory conditions.
Neurodevelopmental disorders (NDDs) are extremely heterogeneous but converge on a number of common molecular processes. Treatment options are limited so far. We will focus on a subset of NDD associated genes/proteins which are involved in the ubiquitin-proteasome system. We will investigate if manipulation of proteasome activity by small molecules can ameliorate phenotypes in Drosophila and/or cell based model systems and thus will gain insights into potential interventional options.
HIV patients coinfected with CMV show increased morbidity and mortality, even on therapy. Despite high coinfection rates, surprisingly little is known about molecular interactions of CMV and HIV. We found that CMV blocks the HIV restriction factor SAMHD1 to facilitate its own replication. This finding finally provides a handle to explain how CMV enhances HIV replication in the host. Thus, we will address the working hypothesis that CMV infection boosts HIV replication by inactivating the SAMHD1.
Recently, we detected Borna disease virus (BoDV-1) as the cause of human fatal encephalitis. Previous studies have addressed the immune response and viral replication, but the host cell receptor of BoDV-1 remained unknown. We will use an unique BoDV-1 patient isolate to search for this receptor, and we will address the possible direct, non-immune related neuropathogenic potential of BoDV-1, as well as antiviral (chemo)therapeutic options, in IPSC derived human neuronal 3D organoid cultures.
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Low-grade epilepsy-associated brain tumours (LEAT) are rare entities with poor interobserver histopathology agreement. The WHO has established an integrated genotype- phenotype classification for most brain tumor entities, but not LEAT. Bioinformatical deep learning algorithms have proven success in extracting such genotype- phenotype information from histopathology slides. Our research proposal evolves around this innovative approach in order to provide diagnostically useful imaging biomarkers.
We demonstrate that dynamic changes in the levels of O-GlcNAcylation are critically required for osteoclastogenesis. Inhibition of this dynamic regulation prevents osteoclast differentiation and ameliorates local and systemic bone loss in experimental arthritis. We now aim to further characterize the signaling pathways regulated by O-GlcNAcylation in inflammatory and non-inflammatory bone loss and to validate targeted modulation of O-GlcNAcylation as a therapeutic option for aberrant bone loss.
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T cells play a major role in complications after allogeneic stem cell transplantation (allo-HSCT). In this projekt we will examine characteristics of T follicular helper cells in patients at different timepoints before and after allo-HSCT and we will correlate them with severe complications (e.g. EBV reactivation or GvHD). With this study, we aim to get more insight in phenotypes and function of Tfh- especially in the context of allo-HSCT:
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Inflammasomes play a pivotal role in the immune response against pathogens, but also in the pathogenesis of inflammatory disorders. Our data indicate that inflammasome activation in DCs is leading to full DC stimulation without induction of pyroptosis. We hypothesize that uncontrolled inflammasome stimulation in DCs might be key component in inflammatory disorders. In this study, we want to elucidate the mechanisms in this specific inflammasome activation in primary DC.
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In this study our goal is to analyze to what extend renal and vascular parameters correlate with histological kidney changes, especially in a population with eGFR rate of more than 60 mL/min/1.73 m². Our crossectional analysis focus on the association of abnormal vascular and renal parameters with histological renal changes. Our longitudinal analysis focus on the association of histological with renal and/or vascular parameters at baseline, with the renal outcome after kidney donation.
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Rheumatoid arthritis is a common autoimmune disease. Anti-citrullinated-protein antibodies (ACPAs) have been identified as key players in RA . But a better understanding of the ACPA-producing B cells and of the transcriptional events in ACPA-specific B cells during the onset of RA is essential. Therefore, we plan to perform an in depth molecular characterization of the dynamic changes occurring inside the ACPA-specific B cell compartment during different phases of RA pathogenesis.
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The main goal in this project is to evaluate the effect of supramagnetic iron oxide nanoparticles for the treatment of head and neck cancer. At first, we will investigate the effects of specific supramagnetic iron oxide nanoparticles on head and neck cancer cell lines. Subsequently, the oncologic potential of supramagnetic iron oxide nanoparticles loaded with chemotheraputics will be analyzed on the various generated cell lines.
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New non-invasive imaging biomarkers for childhood muscular diseases are not yet established. Using multispectral optoacoustic tomography (MSOT), we were already able to detect collagen as a potential biomarker for disease progression monitoring of patients with Duchenne muscular dystrophy. In this experimentell study, we will investigate, which specific optoacoustic spectrum could serve as a biomarker in patients with spinal muscular atrophy.
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The maintenance of healthy bone relies on a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Recent findings indicate that the differentiation and function of osteoclasts can be regulated by certain changes in the cellular metabolism. Accordingly, we demonstrated that the metabolite itaconate inhibits osteoclastogenesis. The major aim of the presented project is the investigation of molecular mechanisms underlying this function of itaconate.
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To date, it is still obscure why in some patients with psoriasis the autoimmune process is restrained to the skin, whereas in other it extends to the joints. We will take advantage of models resembling psoriatic arthritis, with the aim of studying the joint involvement secondary to skin inflammation. The understanding and characterization of the underlying mechanisms involved in the skin-joint axis is pivotal for a better comprehension of the link between physical barriers and autoimmunity
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Non-classical HLA class II molecule HLA-DO largely influences the presented peptide repertoire in HLA class II. HLA-DO expression was shown to play a role in type 1 diabetes, in the generation of neutralizing antibodies to viral infections and in immune responses after allogeneic stem cell transplantation. However, the regulation of HLA-DO is distinct from other class II molecules and remains elusive. We here hypothesize that serotonin receptor signaling plays a role in the regulation of HLA-DO.
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18F-FDG PET/CT is as promising tool for determining treatment response in Ewing Sarcoma (EwS). Standardized uptake values as marker for metabolic tumor activity can be determined in serial scans to determine response to therapy. EwS is characetrised by circulating tumor DNA (ctDNA) that can be quantified from patients' plasma. We intend to use 18F-FDG-PET/CT and ctDNA to determine treatment response in 20 children and adolescents suffering from EwS.
Ferroptosis is a recently identified type of programed necrotic cell death which is tightly regulated by GPX4. In this project the exact role of GPX4 and ferroptosis in myeloid cells under steady state conditions and during Salmonella Typhimurium infection will be investigated. GPX4-regulated ferroptotic cell death might display a new therapeutic target for treatment of acute infections in human patients.
Humans are incapable to regenerate their heart. Cardiac injury results in cardiomyocyte loss due to hypoxia and a changed mechanical micro-environment. Here we propose to determine the potential of polyploid cardiomyocytes, the majority in the adult heart, to contribute to heart repair. We propose to clarify if polyploid cardiomyocytes can be induced to proliferate or whether diploid and polyploid cardiomyocytes differ in regards to stress resistance, cell size, and mechanical properties.
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Mitochondrial function is crucial for maintenance of the adult neural stem/progenitor cell (NSPC) pool. I found that loss of FoxO transcription factors leads to hyperproliferation and depletion of NSPCs and impairs autophagy-lysosome pathway activity. Moreover, loss of FoxOs is associated with mitochondrial dysfunction. I propose to investigate mitochondria as targets of FoxO-dependent autophago-lysosomal degradation, to establish a FoxO-mitophagy axis in the control of adult NSPC function.
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Obesity has become one of the leading global health concerns. Current research suggests a link between obesity, PD-L1 and the microbiome. This project will investigate the role of the microbiome on the function the regulation of adipose tissue T cell responses mediated by innate expression of PD-L1 in mice and humans. Using state-of-the-art RNA and 16S rRNA sequencing, flow cytometry and co-culture systems, we will reveal important mechanisms for the control of adipose tissue inflammation.
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The facial skin is most frequently affected by non-melanoma skin cancer (NMSC). However, the immunological profile of these tumors is still poorly understood. The anticipated ELAN project aims to address this problem by immunohistochemical investigations and may anticipate the establishment of an immunoscore which supplements the TNM classification in prognostic information and therapeutic decision making.
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Germinal center (GC) has been described to contain hypoxic regions linked to B cell class switching. In this project, we will delineate molecular mechanism between HIF-1a-dependent glycolysis and epigenetic modification on IgA class switching region. By studying the IgA response following the C. rodentium infection, we aim to identify the link between the HIF-1a-dependent glycolytic metabolic shift and IgA class switching during microbial infection.
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Breast cancer is the most common cancer in women worldwide. It is hypothesized that in a vicious cycle autotaxin (ATX) secreted by fat tissue influences breast cancer cells in behavior and leads to secretion of inflammatory cytokines which in turn stimulate ATX secretion of fat tissue. Radiotherapy could lead to an amplification of this effect. It is the aim of this study to evaluate the significance of the ATX/LPA-axis and the effect of radiotherapy in different breast cancer subtypes.
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Prognostication in intracerebral hemorrhage (ICH) is biased by self-fulfilling prophecy. We will 1) validate the max-ICH Score, pooling patient data from i) single-center study from Massachusetts General Hospital (Harvard), ii) single-center UKER study, iii) multicenter RETRACE study. We will 2) conduct a prospective multicentre study with randomized controlled prognostic score usage to evaluate physicians prognostic variability & accuracy, optimal prognostic timing, improved outcome measures.
Synaptic plasticity refers to activity-dependent strengthening or weakening of synaptic transmission and underlies memory formation. It can be investigated in-vitro by repetitive network stimulation. In patients with temporal lobe epilepsy, affecting the memory-related hippocampal formation, deficits in memory can occur. We aim to investigate the link between synaptic plasticity and memory impairment by in-vitro field potential recordings from human hippocampus removed during epilepsy surgery.
The focus of the present project is the investigation of Herpes simplex virus type-1 (HSV-1)-mediated modulations of the IL-6 signaling pathway in mature dendritic cells (mDCs). In particular, the underlying molecular mechanisms of reduced IL-6R?, gp130 and STAT3 expression will be analyzed on directly-infected versus uninfected bystander mDCs. Moreover, we will elucidate whether non-infectious L-particles, released from HSV-1-infected cells, are essential/sufficient to induce these modulations.
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To better understand the influence of the early phase of autoimmunity of rheumatoid arthritis (RA) on joint structure, longitudinal observations of pre-RA patients are necessary. High-resolution CT is used to investigate how bone density and structure and biomechanical properties of pre-RA patients develop over time, what influence different biomarker profiles have and what bone characteristics patients developing clinical RA have.
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The oncogenic retrovirus Human T-cell leukemia virus type 1 transmits via cell-cell contacts and viral biofilms seem to constitute a major route of virus transmission. In viral biofilms, extracellular concentrated viral particles are embedded in cocoon-like structures containing collagens (COL) of unknown composition. Here, we hypothesize that the viral transactivator Tax-1 selectively induces expression of COL4 and that COL4 is important for biofilm formation and HTLV-1 transmission.
Previous studies demonstrated a prognostic relevance of several molecular markers in stage T1 bladder cancer. These might optimize risk stratification and decision making with regard to immediate cystectomy or bladder sparing approach. However, these findings have not been validated yet.The goal of the current study is to validate the association of the mRNA expression of these molecular markers with clinical and survival data in a new cohort consisting of stage T1 bladder cancer.
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Physicians practice and opinions regarding continuous sedation until death are to be collected internationally. The German subproject aims to gain a comprehensive overview of the opinions of German palliative physicians by online survey and to link them to their professional background and experiences. The crosscultural comparison might contribute to an internationally binding definition and a more uniform treatment practice.
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YB-1 is expressed in chondrocytes during late embryonic stages and after birth, suggesting a crucial role of YB-1 in chondrogenesis. Little is known about signaling cascades linked to YB-1 mediating ist action. The goal of this study is to investigate YB-1-dependent pathways during chondrogenesis. Particular interest will be paid to MIA-dependent signaling (upstream) and target genes involved in transition to hypertrophy and dedifferentiation (downstream).
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The pathways leading to physiological and maladaptive neuroplasticity are overlapping and strictly controlled by transcriptional regulators such as CtBP1. Following neuronal activity, CtBP1 translocates from nuclei and enables transcription of a number of genes that are involved in memory formation and also seizure generation. Using CtBP1 knock-out mice model, we aim to identify candidate pathways regulating hyperexcitability and develop new intervention mechanisms against these alterations.
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In colorectal cancer (CRC), the transcription factor ZEB1 is upregulated in tumor cells and tumor-associated macrophages. As only its tumor-promoting role in tumor cells is known, we are analyzing myeloid-specific ZEB1 knockout mice. Our preliminary data suggest that ZEB1 plays a role in macrophage polarization, intestinal inflammation and CRC growth. Here, we will explore novel functions of ZEB1 in immune homeostasis, macrophage plasticity, immune-modulation in CRC and colitis-associated CRC.
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Recently we identified de novo variants in FBXO11, encoding a subunit of an E3-ubiquitin ligase complex, as causative for a neurodevelopmental disorder (NDD). The goal of this grant is to characterize the role of FBXO11 in NDDs. With the model organism Drosophila melanogaster anatomical studies of synapses and behavioral assays will be performed. Additionally effects of patient mutations will be tested in cell-based assays and target proteins of FBXO11 will be identified using AP-MS.
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The aim of our project is to descramble the role of the purinergic receptor P2Y2R in the context of Ca2+-dependent Cl--secretion as a main course of cyst growth in ADPKD. We will use our novel PKD1-deficient 3D cyst model and micropuncture cysts to analyse the effects of luminal ATP as well as the P2 inhibitor Suramin. In addition, we will test for the impact of P2Y2R knockout on the cystic burden in our PKD1 knockout mouse model and determine the therapeutic potential of Suramin in vivo.
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Epidemic models are used to analyse and forecast the spread of infectious diseases. Specialized regression methods for surveillance data allow us, for example, to evaluate socio-demographic and environmental factors. The aim of this project is to extend such statistical modelling frameworks for two types of applications: multivariate time series of proportions and spatio-temporal point patterns. All methodological developments are accompanied by implementations in open-source software.
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The genetic background of chronic kidney disease in adults in poorly investigated. This study aims to identify novel candidate genes by Whole Exome Sequencing in adult patients with chronic kidney disease. Transcriptome analysis of patient specific primary cells will be employed to functionally characterize these candidate genes. CRISPR/Cas9 based zebrafish experiments will transfer the in vitro findings in an animal disease model.
The tumor microenvironment (TME) plays a pivotal role in tumorigenesis, prognosis and therapy. SPARCL1 is a vascular derived anti-tumorigenic factor that counteracts CRC tumorigenesis in a TME-dependent manner. Preliminary results indicate that SPARCL1 regulates ERK phosphorylation and subcellular localization in endothelial and CRC cells. This project aims to elucidate the signaling pathways by which SPARCL1 transmits its anti-proliferative and anti-angiogenic functions, mainly focusing on ERK.
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AML is the most common acute leukemia in adults. Emerging evidence suggests that immune alterations favor leukemogenesis and relapse. Myeloid derived suppressor cells (MDSCs) are mediators of tumor immune escape. Here, we aim to decipher the interconnection between metabolic reprogramming and MDSC abundance in AML and to unravel the role of AML-derived exosomes in this context. A better understanding is key for improving immune-based therapeutic approaches in AML.
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The objective of this study is to identify the role of regulatory proteins of voltage-gated sodium channels (ß subunits) as potential contributors and new therapeutic targets of pain. Main focus of this work will be on mutations of ß1 and ß3 that have recently been found in patients suffering from the pain syndrome erythromelalgia. Using human stem cell-derived nociceptors these mutations will be functionally characterised with electrophysiological and molecular biology methods.
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The role of IL-3 in the pathogenesis of inflammatory bowel diseases (IBD) has not been explored so far. Preliminary data show that the course of oxazolone colitis is aggravated in IL-3 deficient mice vs. controls and that the expression of IL-3 is significantly increased in active ulcerative colitis. Therefore, this project is designed to address the role of IL-3 in experimental colitis and human IBD. This could lead to the identification of novel therapeutic targets for the treatment of IBD.
The transverse tubular system (t-system) of ventricular cardiomyocytes is crucial for cardiac contractility. Stabilizing t-system structure is a target of therapy and prevention because the t-system depletes or structurally declines in heart failure. However, mechanisms of t-system regulation remain largely unknown. Our preliminary data suggest t-system regulation by corticoid receptor signaling. The proposed project shall identify underlying signaling pathways and associated proteins.
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GATA4 is expressed in the intestinal epithelia and regulates metabolic functions in physiological states. We have shown that a microbiota-derived signal regulates epithelial GATA4. Epigenetic silencing of GATA4 frequently occurs in colon cancer patients. However, its role in bridging gut barrier, inflammation and carcinogenesis remains poorly defined. We seek to identify pathways and strategies to restore GATA4 in cancer to provide new therapeutic alternatives in the treatment of colon cancer.
Neutrophil granulocytes play a central role in innate immunity, but their function regarding pathogenesis of autoimmune diseases like rheumatoid arthritis is poorly understood. Previous studies were restricted to cell-unspecific models or cell culture experiments. Thus, we aim to study this cell type via novel cutting-edge imaging techniques and newly available high specific mouse models in vivo.
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Preclinical and first clinical data suggest that treatment with recombinant immunotoxin (rITs) targeting mesothelin induced anti-tumor immunity in patients. The goal of this study is to test CD22-targeting rITs for their capacity of inducing anti-lymphoma immunity in a newly established syngeneic mouse model. The model will be used to understand molecular mechanisms central to the lymphoma-host-interaction and to optimize immune-modulating combination treatment based on lymphoma-targeting rITs.
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We are excited by developing and using physics-based approaches to study biological processes. In particular, we like to observe how enzymes process nucleic acids, e.g. DNA or RNA, and proteins. These processes are at the heart of the replication, expression and maintenance of the genome and are therefore key aspects of the life cycle of every organisms. We use single-molecule techniques such as magnetic tweezers and fluorescence microscopy to investigate the dynamics of intermolecular motions during…
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The Junior Group is focused on the mechanisms that regulate cancer plasticity and at studying the epithelial-to-mesenchymal transition, the cancer stem cells and the association between cancer differentiation and sensitivity to chemotherapy. We aim at identifying novel mechanisms that regulate the plasticity of cancer by the use of several cell and molecular biology techniques, mouse models, and the analysis of human samples as well as by ?omics and high-throughput approaches.
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The Junior Group is focused on the mechanisms that regulate cancer plasticity and at studying the epithelial-to-mesenchymal transition, the cancer stem cells and the association between cancer differentiation and sensitivity to chemotherapy. We aim at identifying novel mechanisms that regulate the plasticity of cancer by the use of several cell and molecular biology techniques, mouse models, and the analysis of human samples as well as by ?omics and high-throughput approaches.