Darstellung eines einzelnen Forschungsbereichs, Publikationen nach Jahr sortiert
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Advanced Projects
The IZKF offers research grants in all major research areas of the Faculty of Medicine, i.e. immunology and infection research, renal and vascular research, neurosciences and tumor research. The funding period is 30 months.
Projects:
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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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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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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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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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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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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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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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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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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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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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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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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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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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We will define the relevance of VRAC for T cell function in colitis and validate VRAC as a potential target for IBD therapy. Our initial data point to a functional role of VRAC in T cell-driven colitis and implicate that VRAC modulates immunometabolism and mechanical properties of T cells. Using VRAC KO mice and IBD tissue samples, we will elucidate the colitis-regulating capacity of VRAC in T cells, identify modulators of VRAC expression and define its interplay with T cell immunometabolism.
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We found in mice and humans a plasma cell population with high surface sialylation. We hypothesize that this population represents activated plasma cells that experience ER stress and await survival signals. We will characterize these cells in mice and humans regarding ER stress, survival, signalling and metabolism, analyse plasma cells from mice with B cell intrinsic elevated ER stress, investigate niche support and how surface sialylation influences plasmablast/ plasma cell fate.
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Allergic asthma (AA) is an inflammatory lung disease. At present it is unclear how macrophage populations in the lung are altered at different stages of allergic inflammation (onset, acute phase, resolution). We will use a mouse AA model to address the population dynamics of macrophages using fate mapping mice, interrogate the role of IL-4/IL-13 and activating or inhibitory Fc receptors, and study the impact of macrophages on their tissue environment with mouse and human lung organoids.
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Heterozygous variants in the transcription factor SOX11 have been linked to a rare neurodevelopmental syndrome featuring intellectual disability and microcephaly. This project investigates the novel concept that SOX11 plays an essential role for mitotic spindle function through a non-transcriptional mechanism and that disruption of this mechanism contributes to the pathogenesis of SOX11-linked neurodevelopmental disorders.
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Amino acids such as arginine and proline influence the immune system as well as different microbial organisms. However, the influence of both amino acids on immune defense and microbiota-mediated colonization resistance or on Salmonella virulence is unknown. Therefore, we will characterize a) the influence of arginine-dependent microbiota on Salmonella infections and b) the role of proline in Salmonella virulence and anti-bacterial immune response.
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Primary Sjögrens syndrome (PSS) is an autoimmune disease causing chronic inflammation of exocrine glands, dry mouth and eyes. Our preliminary data identify RIP kinases as novel regulators of salivary gland homeostasis and potential factors in PSS. Inducible RIP kinase-deficient mice develop PSS-like disease and implicate this kinase in immune regulation and epithelial homeostasis within the salivary gland. This proposal aims to clarify the role of RIP kinases in the salivary gland and in PSS.
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