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

项目摘要/摘要 这是艾米博士为K23指导的以患者为导向的研究职业发展奖的重新提交 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- 心脏病科学家，专门研究心血管遗传学。这个应用程序的目的是支持Dr。 Kontorovich的职业生涯从指导研究员过渡到独立调查员 心血管基因组学与心肌炎。急性心肌炎(AM)是导致心力衰竭的最常见原因 在其他方面，儿童健康，是成人扩张型心肌病的重要原因。使役 嗜心病毒在环境中很常见，但大多数接触病毒的人不会患上AM和 那些有变化无常的疾病表情的人。PI最近表明，这个变量响应与 对于心肌病的遗传变异，这一发现将AM的范例转移到了人类基因的领域 疾病。这里的研究策略建议探索影响易感性的遗传因素 以及通过对650名AM患者的下一代测序(NGS)得出的AM结果，这是 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) 定义基因状态和临床严重程度之间的关系以及3)使用对照建立病毒性AM模型 并对“心肌病”人诱导的多能干细胞来源的心肌细胞进行病毒作用的研究 在不同遗传背景的细胞中的感染。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，有可能识别新的遗传风险和预后因素 上午好。K23奖将通过支持四个基本领域的培训来支持这些目标的实现：1) 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) 病毒学和核糖核酸病毒和4)职业发展。职业发展计划需要正式的 课程、工作坊、研讨会、会议和由初级导师Bruce Gelb博士领导的辅导会议， 儿科学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 Fernandez-Sesma博士，微生物学教授，病毒学和RNA病毒专家， 和共同的小学导师英加·彼得博士，遗传学和基因组科学教授，在 遗传流行病学，以及其他顾问和合作者。研究结果将形成 在K23授权期结束前申请R01的基础，这将侧重于基于细胞的研究 筛选个体化药物为主的治疗药物，小鼠模型的特定“心肌炎基因”和更大 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.