Characterization and function of OPA1 in intestinal epithelial homeostasis and the pathogenesis of inflammatory bowel disease

• Applicant: Professor Dr. Christoph Becker
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510624836

Inflammatory Bowel Diseases (IBD, Crohn’s disease and ulcerative colitis) are common inflammatory diseases affecting more than 400.000 patients in Germany alone. Since the cause of IBD is largely unknown, there is currently no causative therapy available for IBD patients. Our previous studies provided functional evidence that a primary defect in cell death regulation of the intestinal epithelium can cause barrier dysfunction, microbial translocation into the bowel wall and chronic gut inflammation with similar features as seen in IBD patients. We also demonstrated that epithelial cells death pathways are tightly regulated by both signals from the microbiome and the immune system in the steady state gut. Mitochondria play a crucial role in cell death regulation and the dynamics of mitochondrial fission and fusion in cells has recently been shown to be connected to immune and tissue homeostasis. Although functional data regarding the role of these processes in gut immune homeostasis and IBD are sparse, our unpublished data imply an important role for OPA1, a key regulator of mitochondrial fusion, for intestinal immune homeostasis and the pathogenesis of IBD. Our preliminary data provide evidence of mitochondrial alterations in epithelial cells of IBD patients. Moreover, OPA1 was found to be downregulated in both experimental colitis in mice and human IBD. In support of an important functional role of OPA1, newly generated mice specifically deficient in OPA1 in the intestinal epithelium spontaneously developed chronic intestinal inflammation associated with increased epithelial cell death. Based on these preliminary data, we hypothesize that OPA1 has a profound impact on the development of intestinal inflammation and that modulating OPA1 and mitochondrial dynamics might have therapeutic potential in IBD. To evaluate this hypothesis and to decipher the consequences of diminished OPA1 expression on mitochondrial dynamics, epithelial cell homeostasis and intestinal inflammation, we aim to study the functional role of epithelial OPA1 for intestinal tissue homeostasis and gut inflammation using mice with altered OPA1 expression. Further, we will focus on revealing the functional role of OPA1 for epithelial barrier functions and assess changes on the level of mitochondria caused by OPA1 deficiency. Finally, we will evaluate the impact of OPA1 on the development and progression of human IBD and further explore the potential therapeutic value of preclinical modulation of OPA1 expression and function. Our long-term goal is to evaluate the innovative concept that a dysfunction in mitochondrial dynamics is a driver of IBD pathogenesis.

• DFG Programme: Research Grants