The role of Axl signaling in intestinal fibrosis - Project Summary Crohn's disease (CD) is a highly prevalent form of inflammatory bowel disease (IBD) much in need of further understanding. Most patients who are diagnosed with CD will develop complications from intestinal fibrostenosis, yet there are no medical therapies for the treatment of intestinal fibrosis. The lack of therapy is in large part due to our incomplete understanding of the underlying pathophysiological mechanisms of intestinal fibrosis. We have shown that AXL, a tyrosine kinase, is a pro-fibrotic mediator in the intestine. AXL is a promoter of cellular proliferation, migration, epithelial-mesenchymal transition, and has been shown to be involved in the development of fibrosis in other organs such as the liver and kidney. In ongoing work, we have found that in the intestine AXL is primarily expressed by stromal cells, while the primary ligand of AXL (GAS6) is expressed primarily by the epithelial cells. Further, we have discovered that the intestinal epithelium responds to acidosis and hypoxia, which are both key features of an inflammatory microenvironment, by acutely decreasing expression of GAS6. These findings show that AXL signaling can promote intestinal fibrosis, and suggest that GAS6/AXL signaling is a likely mode of epithelial-stromal cross talk in response to the luminal microenvironment. Unraveling the intricacies of this signaling and how it contributes to intestinal responses, and ultimately fibrosis, is the intent of this proposal. The ultimate goal is that this work will lead to novel medical therapies for intestinal fibrosis that target the AXL signaling pathway. The applicant, Dr. Steiner, has established a scientific niche in which to build a foundation for independent research on the cellular and molecular mechanisms of intestinal fibrosis. Dr. Steiner and his mentor, Dr. Colgan, assembled a mentorship committee to regularly meet as a group with Dr. Steiner throughout the duration of the award to provide feedback on the research, critique the research plans, monitor publications, and provide career advice. Drs. Colgan and Steiner have identified coursework relating to each aim to facilitate expansion of Dr. Steiner's foundation of knowledge in fundamental molecular biology, cellular biology, and use of murine model systems. Dr. Steiner will submit his work to present at conferences specific to his research to share his research and network with colleagues and potential collaborators, and get valuable feedback from the scientific community. Dr. Steiner's development will benefit from continued participation in the Mucosal Inflammation Program (MIP), a multi-disciplinary, multi-departmental program initiated to study mechanisms of mucosal inflammation and resolution. The MIP fosters a unique lab environment for collaboration between physician scientists, clinicians, and research scientists, and works to establish an environment for young investigators to flourish and develop. The facilities and resources available to and development plan built for Dr. Steiner provide an ideal environment and path for his successful transition to independence.
