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

项目概要/摘要 这是由Amy博士重新提交的K23指导患者导向研究职业发展奖 R. Kontorovich（PI）在西奈山伊坎医学院（ISMMS）。康托洛维奇医生是一名临床医生 心血管遗传学专家。此应用程序的目的是支持博士。 Kontorovich的职业生涯从指导研究员转变为独立调查员， 心血管基因组学和心肌炎。急性心肌炎（AM）是心脏衰竭的最常见原因， 是成人扩张型心肌病的重要病因。致病 亲心病毒在环境中很常见，但大多数暴露个体不会发生AM， 那些有不同疾病表现的人。PI最近表明，这种可变响应与 到心肌病遗传变异，这一发现将AM的范式转移到人类遗传学的领域。 疾病本文的研究策略建议探索影响易感性的遗传因素， 通过下一代测序（NGS）对650名AM受试者进行AM的结果，这是最大的队列， 约会具体目标是：1）确定AM受试者中遗传变异的频率和类型，2） 定义基因型状态和临床严重性之间的关系，以及3）使用对照对病毒AM进行建模 和“心肌病”人类诱导多能干细胞衍生的心肌细胞，以研究病毒对心肌细胞的影响。 感染不同遗传背景的细胞。这种方法利用NGS数据、基因组分析和 一种基于干细胞的疾病模型，有可能确定新的遗传风险和预后因素， AM. K23奖将通过在四个基本领域开展培训来支持实现这些目标： 高级遗传学和基因组数据分析，2）心血管遗传学和心肌病，3） 病毒学和RNA病毒和4）职业发展。职业发展计划需要正式的 课程，讲习班，研讨会，会议和指导会议由主要导师博士领导。布鲁斯盖尔布， 儿科和遗传学与基因组科学教授，心血管疾病遗传学的领导者，共同 主要导师Ana Fernando-Sesma博士，微生物学教授，病毒学和RNA病毒专家， Inga Peter博士，遗传学和基因组科学教授，在以下方面拥有丰富的专业知识： 遗传流行病学，以及其他顾问和合作者。研究结果将构成 K23奖励期结束前R 01申请的基础，将重点关注基于细胞的研究， 筛选个性化的药物为基础的疗法，小鼠模型的特定“心肌炎基因”和更大的 临床研究。

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.