Elucidation of the role of human genetic factors underlying viral myocarditis susceptibility

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PROJECT SUMMARY / ABSTRACT This is a resubmission for a K23 Mentored Patient-Oriented Research Career Development Award by Dr. Amy R. Kontorovich (PI) at the Icahn School of Medicine at Mount Sinai (ISMMS). Dr. Kontorovich is a clinician- scientist in Cardiology specializing in cardiovascular genetics. The purpose of this application is to support Dr. Kontorovich’s career transition from mentored researcher into independent investigator in the fields of cardiovascular genomics and myocarditis. Acute myocarditis (AM) is the most common cause of heart failure in otherwise healthy children and is a significant cause of dilated cardiomyopathy in adults. Causative cardiotropic viruses are common in the environment but most exposed individuals do not develop AM and those who do have variable disease expression. The PI has recently shown that this variable response relates to cardiomyopathic genetic variants, a finding that shifts the paradigm of AM into the realm of a human genetic disease. The Research Strategy herein proposes to explore the genetic factors that influence susceptibility to and outcomes of AM through next-generation sequencing (NGS) of 650 subjects with AM, the largest cohort to date. Specific aims are: 1) To determine the frequency and types of genetic variants in subjects with AM, 2) To define the relationship between genotype status and clinical severity and 3) To model viral AM using control and “cardiomyopathic” human induced pluripotent stem cell-derived cardiomyocytes to study the effects of viral infection in cells of differing genetic backgrounds. This approach, leveraging NGS data, genomic analysis and a stem cell-based model of disease, has the potential to identify novel genetic risk and prognostic factors for AM. The K23 award will support achievement of these aims by enabling training in four essential domains: 1) Advanced Genetics and Genomic Data Analysis, 2) Cardiovascular Genetics and Cardiomyopathies, 3) Virology and RNA Viruses and 4) Career Development. The Career Development Plan entails formal coursework, workshops, seminars, conferences and mentoring sessions led by primary mentor Dr. Bruce Gelb, Professor of Pediatrics and Genetics & Genomic Sciences, a leader in genetics of cardiovascular disease, co- primary mentor Dr. Ana Fernandez-Sesma, Professor of Microbiology, an expert in virology and RNA viruses, and co-primary mentor Dr. Inga Peter, Professor of Genetics & Genomic Sciences with vast expertise in genetic epidemiology, as well as additional advisors and collaborators. Findings from the research will form the basis for an R01 application prior to the end of the K23 award period, which will focus on cell-based studies for screening personalized medicine-based therapeutics, mouse models of specific “myocarditis genes” and larger clinical studies.