Elucidating the Role of Regulatory T cells in Protecting Epithelial Stem Cell Niches

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PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year research and career development plan that will enable Dr. Jarish Cohen to achieve his long-term goal of becoming an independently funded physician-scientist studying how regulatory T cells (Tregs) protect cutaneous epithelial stem cells during development, homeostasis, and disease. Currently, very little is known about the mechanisms skin-resident immune cells use to safeguard cutaneous epithelial stem cells in inflammatory dermatoses and alopecias. The proposed research will focus on uncovering the mechanisms by which Tregs protect hair follicle stem cells (HFSC) from attack by autoreactive T cells. Dr. Cohen has generated a novel experimental in vivo model of Treg-mediated protection of HFSC from autoimmune attack, that closely resembles a highly morbid form of human scarring alopecia. Additionally, he has pioneered a highly innovative topical technique to delete genes specifically in skin-resident Tregs, which will allow him to resolve organ-specific mechanisms of Treg-mediated immunoprotection of stem cells. In Aim 1, Dr. Cohen will elucidate the spatial and temporal kinetics of Treg-mediated HFSC protection and dissect the mechanism of skin Treg localization to the HFSC niche. Aim 2 will focus on elucidation of the distinct mechanisms that Tregs in the skin and lymph nodes employ to safeguard against HFSC destruction. In Aim 3, Dr. Cohen will leverage comprehensive transcriptomic and cutting-edge imaging technologies to identify molecules and pathways of Treg dysfunction and altered patterns of Treg localization in human scarring alopecias. The aggregate data will provide a major advancement in our understanding of how Tregs promote immune tolerance of epithelial stem cells and have the potential to identify novel therapeutic strategies to treat human dermatoses. During his post-doctoral work and as a Clinical Instructor in the University of California, San Francisco (UCSF) Dermatopathology Service, Dr. Cohen has strategically sought out additional training and mentorship in cutaneous immunology. Under the mentorship of Dr. Michael Rosenblum, M.D., Ph.D., an expert in skin Treg biology, the candidate, co-mentors (Drs. Jason Cyster, Ph.D., and Ophir Klein, M.D., Ph.D.), and scientific advisors (Drs. Boris Bastian, M.D., Ph.D., and Abul Abbas M.D., Ph.D.) have developed a career development plan for Dr. Cohen to gain additional experience in state of the art immunology and cutting-edge imaging techniques, biostatistics, epithelial stem cell biology, and scientific communication. To enhance Dr. Cohen's training, a multidisciplinary advisory committee consisting of mentors, scientific advisors, and Dr. Jayanta Debnath, M.D., chair of the UCSF Department of Pathology, will meet biannually to review his progress and support his career development. The proposed training program draws on the combined resources of the Rosenblum Laboratory, the UCSF Immunology Training Program, and the UCSF Departments of Dermatology and Pathology. This will provide an ideal setting for Dr. Cohen's transition to an independent investigator.