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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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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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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 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 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 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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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 Nsp’s 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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Parkinson’s 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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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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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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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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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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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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