Defining the role of Pi16-expressing fibroblasts in mouse and human fibrosing skin disease

PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year research and career development plan that will enable Dr. Maxime Kinet to achieve his long-term goal of becoming an independently funded physician-scientist studying how different fibroblast subsets contribute to tissue homeostasis and fibrosing diseases. Currently, very little is known about how individual fibroblast subsets, identifiable in healthy tissues, differ in their responses and contribution to fibrosing skin disease. The proposed research will focus on uncovering the mechanisms by which the Pi16+ fibroblast subset, common to many organs in mammals, responds to and reduces fibrosis. Dr. Kinet will use a novel, fibroblast-subset-specific Pi16CreERT2 line to study this conserved subset. Additionally, he will apply this Cre line alongside a highly innovative in vivo CRISPR/Cas9 technique to enable interrogation of any genetic pathway in these cells. In Aim 1, Dr. Kinet will elucidate how Pi16-expressing fibroblasts molecularly respond to a fibrotic stimulus. Aim 2 will focus the mechanisms used by Pi16-expressing fibroblasts to reduce fibrosis in the overlying skin. In Aim 3, Dr. Kinet will leverage comprehensive single-nuclear and spatial transcriptomic technologies to identify how Pi16-expressing fibroblasts change in human fibrosing skin disease. The aggregate data will provide a major advancement in our understanding of how Pi16-expressing fibroblasts, a conserved subset across tissues and species, respond to and regulate fibrosis. During his post-doctoral work and as Assistant Professor in the University of California, San Francisco (UCSF) Rheumatology Division, Dr. Kinet has strategically sought out additional training and mentorship in cutaneous immunology and fibrosis. Under the primary mentorship of Dr. Michael Rosenblum, an expert in skin Treg biology, the candidate, co-mentors Drs. Dean Sheppard and Ari Molosky, and scientific advisors Drs. Julie Zikherman and Francesco Boin have developed a career development plan for Dr. Kinet to gain additional experience in state-of-the-art immunology and cutting-edge transcriptomic profiling, biostatistics, and scientific communication. To enhance Dr. Kinet’s training, a multidisciplinary advisory committee consisting of mentors and scientific advisors 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. Kinet’s transition to an independent investigator.