Project Summary/Abstract This proposal describes a 5-year training program for the development of an academic career with a research focus on immune regulatory mechanisms that govern epidermal stem cell differentiation in inflammatory skin disease. Dr. Mathur obtained an M.D. and Ph.D. from Indiana University School of Medicine's MSTP program. His graduate work focused on the transcriptional regulation (including roles for Stat3, Stat4, and T-bet) of IL- 17-secreting CD4+ T cells (Th17 cells). These cells have now been implicated in the pathogenesis of numerous inflammatory diseases including psoriasis, arthritis, and multiple sclerosis. This along with his clinical training in dermatology and fellowship training in pediatric dermatology has uniquely prepared him to examine how skin-resident regulatory T cells function to influence stem/progenitor cell differentiation and epidermal regeneration in inflammatory skin disease. Dr. Mathur recently graduated from a dermatology residency at Indiana University. Thereafter, he was recruited to UCSF's Physician-Scientist Training Program, an NIH supported T32 program combining clinical training in Pediatric Dermatology with a post-doctoral research fellowship. During his post-doctoral work and over the past year as a junior faculty member in UCSF's Department of Dermatology, Dr. Mathur has strategically sought out additional training and mentorship in cutaneous immunology, skin barrier function and epidermal stem cell biology. Through the proposed training program, he will expand upon his expertise in these areas as well as gain skills critical for professional development, ethical conduct of research, statistical analysis, and clinical care of pediatric patients with inflammatory skin disease. Dr. Mathur's goal is to become an independent investigator studying the mechanisms responsible for establishing and maintaining immune homeostasis in the skin. He will accomplish this through coursework, participation in seminars and conferences, national presentations and engagement in a mentored research project. Currently, little is known about how skin-resident immune cells influence epidermal stem cell function in inflammatory skin diseases. Nevertheless, stem/progenitor cell activation is necessary to repair skin barrier defects following inflammatory insults. The proposed research will focus on uncovering the cellular and molecular mechanisms by which regulatory T cells (Treg) support stem cell activation and epidermal regeneration. Dr. Mathur has made the novel observation that skin Tregs are abundant and co-localize with a population of epidermal stem cells that reside within the hair follicle bulge (HFSCs). Furthermore, Tregs influence HFSC activation, which supports keratinocyte differentiation and skin barrier repair after inflammatory skin injury. In the proposed experiments, Dr. Mathur will elucidate how skin-Tregs promote epidermal regeneration. Using sophisticated mouse model systems, he will dissect how regulatory T cells control epidermal cell differentiation both at the cellular and molecular levels. The aggregate data will provide a major advancement in our understanding of how Tregs promote epidermal barrier homeostasis, and have the potential to establish a foundation for novel therapeutic strategies for inflammatory skin disease. Dr. Mathur will benefit from a co-mentorship model that draws on the experience of senior faculty members as well as the resources and scientific expertise of a promising junior faculty member. Drs. Richard Locksley M.D. and Abul Abbas M.D. will be the senior mentors guiding Dr. Mathur's scientific and career development. Dr. Locksley is an HHMI investigator, Professor of Medicine at UCSF, and a preeminent scientist whose laboratory focuses on allergic inflammation in barrier tissues including skin, lung and intestines. Dr. Abbas is Professor and Chairman of the Department of Pathology at UCSF and a world-renowned leader in the field of immune tolerance. Their combined record of mentoring postdoctoral fellows and graduate students is outstanding. The research will be conducted in the laboratory of Dr. Michael Rosenblum, who is an Assistant Professor in the Department of Dermatology and a former trainee of Dr. Abbas. Dr. Rosenblum will provide the resources and space required for the proposed work as well as guidance on skin-specific aspects of immune regulation. To enhance Dr. Mathur's training, a scientific advisory committee consisting of all three co-mentors as well as Dr. Theodora Mauro, a senior physician-scientist and cutaneous biologist who has expertise in keratinocyte biology and barrier function, Dr. Ophir Klein M.D., Ph.D., a physician-scientist with expertise in adult stem cell and regenerative biology, and Dr. Bruce Wintroub, chair of the UCSF dermatology department, will meet twice yearly 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, The UCSF Center of Regeneration Medicine and Stem Cell Research, and the UCSF Department of Dermatology. This will provide an ideal setting for Dr. Mathur's transition to an independent investigator.

Project Narrative Our skin acts as a barrier to protect us from water loss and pathogen invasion, which is process critically dependent on epidermal stem cells that constantly regenerate the epidermis. Skin barrier disruption is linked to both chronic inflammation and stem cell activation; but how these two processes are related in inflammatory skin diseases is unknown. Our research is focused on trying to understand how the immune system influences epidermal stem cell differentiation that results in skin barrier repair, in order to develop novel therapeutic strategies to treat skin conditions that stem from a breakdown in skin barrier function.