Contribution of Adipocytes and Adipose Secreted Factors to Fibrosis in Systemic Sclerosis

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Project Summary This K08 career development award will provide Dr. Benjamin Korman M.D. the needed mentored training to ensure that he develops into an independent researcher who will utilize both laboratory-based experimental approaches and omics and bioinformatics to better understand the pathogenesis of systemic sclerosis (SSc). Candidate Dr. Korman is an Instructor in Medicine-Rheumatology at Northwestern University. He is dedicated to a career in academic rheumatology and has shown commitment to translational research. He completed his rheumatology fellowship at Northwestern one year ago, and has spent three years in his mentor Dr. John Varga’s laboratory where he has generated exciting preliminary data which support his current proposal. In addition to a robust publication record (15 publications, 12 original high-impact research articles including 3 first-authored original research articles, one co-first authored research article, and 3 first-authored review articles), in the last four years, he has also been successful in obtaining funding including a T32 training grant, an individual NIAMS F32 award, and an institutional BIRCWH K12 award which currently supports his work. Research Plan The research plan outlined builds on recent evidence that adipocytes modulate skin fibrosis, play a key role in SSc pathogenesis, and that a disruption in normal adipose-fibroblast homeostasis leads to unhealthy levels of adipose secreted factors in SSc. To test the hypothesis that adipocyte dysfunction is a fundamental process in SSc pathogenesis, in Aim 1, Dr. Korman will assess how mouse models of ablation or expansion of adipose tissue impact scleroderma, whether adipocytes are necessary to resist skin fibrosis, and if secreted factors mediate this effect. In Aim 2, he proposes to use ex vivo cultures of SSc fibroblasts treated with adipocyte derived factors to determine the mechanism as to how adipocytes exert their effects and which secreted factors may be relevant to SSc. To better understand the cellular regulation of these processes, he will utilize RNA-Seq to assess whole genome expression and bioinformatics to interpret this data. If successful, this work should lead to the development of biomarkers and therapeutics for SSc, a disease which currently lacks both. Career Development Plan Dr. Korman will achieve his career goals through a career development plan that consists of formal coursework, and intensive mentorship that will teach him to independently perform translational research which utilizes mouse models of fibrosis, ex vivo culture systems, RNA-Seq, and bioinformatics. His primary mentor is Dr. John Varga, a world expert in SSc and fibrosis with over 20 years of continuous NIH funding, hundreds of seminal papers in SSc, and an outstanding record of mentoring. Dr. Varga will ensure that Dr. Korman obtains the knowledge and appropriate laboratory skills necessary to head a lab focused on SSc. His co-mentor Dr. Davuluri is the foremost expert in bioinformatics at Northwestern and will provide both formal didactic training in informatics as well as regular mentoring to ensure that Dr. Korman becomes an expert in utilizing omic technologies and modern computational techniques. Dr. Korman’s career development will be based on work toward four well-defined and attainable goals. These include 1) to develop the skills to design and execute mechanistic research using in vivo and ex vivo systems, 2) to learn how to utilize, computationally analyze, and interpret the results of high-throughput omic data, 3) hone his leadership, organizational, communication, and grant writing skills and 4) to publish research study results and obtain independent R01-level funding. Institutional Environment The work will be accomplished at Northwestern University which is an ideal training environment. Northwestern provides Dr. Korman with 1) dedicated support from the Division of Rheumatology and Department of Medicine; 2) a multidisciplinary team of mentors and collaborators; 3) courses, seminars, and scientific meetings relevant to his career development; 4) a research infrastructure that includes lab space and equipment, multiple relevant core facilities, and bioinformatics support; 5) a wide variety of career development workshops; and 6) at least 75% protected time with one half-day of SSc-focused rheumatology clinic weekly and only one-two weeks of inpatient rheumatology consult duty per year. Summary Dr. Korman’s career goal is to become an independent translational researcher who utilizes state-of-the-art laboratory and computational techniques to better understand the pathogenesis of SSc. In the short-term, he will complete the experiments outlined in the proposal, submit study results for publication, and continue to develop expertise in laboratory-based cellular and molecular biology, and integration of high-throughput platforms with laboratory data using bioinformatics. In the long-term, this work will form the basis for an R01 and propel Dr. Korman to become a leader in the systems biology of SSc who will leverage the skills he obtains during this award to develop precision-medicine strategies that can effectively treat patients with SSc.