Regulation of intestinal lipid metabolism by type-3 immune cytokine - PROJECT SUMMARY/ABSTRACT This application details a five-year research and career development plan to facilitate the transition of Dr. Yajing Gao from a post-doctoral fellow to an independent faculty position. Dr. Gao received her PhD in Immunology from UT Southwestern Medical Center focusing on mucosal lymphocyte differentiation. She then completed 4 years of post-doctoral training in lipid metabolism and physiology at University of California, Los Angeles. The mentored phase (K99) of the award will be completed under the continued guidance of Dr. Peter Tontonoz, an internationally recognized leader in lipid metabolism with over 25 years of mentorship in post-doctoral career development. Dr. Gao’s transition to independence will be supported by Dr. Tontonoz, co-mentor Dr. Martín, and a diverse advisory team with scientific expertise related to the proposed research, as well as a track record of promoting trainees’ independence. The applicant has identified targeted training objectives, including technical and didactic coursework and conferences to overcome scientific deficiencies in gastroenterology and metabolic analysis, to improve professional skills in grant writing, project management, and mentoring, and to secure an independent faculty position. Under the exceptional institutional environment for metabolism research and career development at UCLA, Dr. Gao will have access to top-tier training resources, core facilities, seminars, and exceptional collaborators to achieve her career goals. Nutrient deficiencies often accompany chronic gut inflammation and immune dysfunction. Yet molecular insights pertaining to the immunological regulation of nutrient uptake are lacking. The applicant’s recent work identified a connection between hyperactive type-3 immune cells and intestinal metabolic imbalance. Preliminary studies demonstrate that the mucosal type-3 cytokine directly controls the nutrient-handling abilities of the enterocytes. Aim-1 will identify signaling components and the underlying mechanism by which type-3 cytokine modulates enterocyte functionality, and test a promising strategy to correct this metabolic deficiency. In Aim-2, the candidate will obtain training to establish a mass-spectrometry-based approach to measure longitudinal nutrient flux in the intestine accompanying dietary change and delineate the contributions of distinct type-3 lymphocyte populations. Aim-3 will investigate the functional significance of the cytokine receptor in enterocytes and test the impacts of its loss on systemic metabolism. These studies will uncover fundamental enterocytic pathways governing nutrient flux, which is sensitive to the immune microenvironment, and inform the therapeutic utility of these targets for various inflammation-related digestive disorders. Through this award, Dr. Gao will develop scientific and professional skills in order to become an independent investigator at the intersection of mucosal immunology and intestinal physiology.
