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

阐明人类遗传因素在病毒性心肌炎易感性中的作用

基本信息

批准号：
10439445
负责人：
Amy R. Kontorovich
金额：
$ 19.03万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-06 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439445
关键词：
Achievement Acute Myocarditis Adult Age Arrhythmogenic Right Ventricular Dysplasia Autopsy Biological Assay Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Cardiovascular Diseases Cardiovascular system Career Mobility Cells Cessation of life Child Chronic Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats DNA DNA Sequence Alteration Data Data Analyses Deterioration Development Plans Dilated Cardiomyopathy Disease Disease model Duchenne cardiomyopathy Duchenne muscular dystrophy Educational workshop Electrophysiology (science)Enrollment Environment Europe Family Family member Fostering Frequencies Gene Mutation Gene Targeting Genes Genetic Genetic Determinism Genetic Diseases Genetic Risk Genomics Genotype Health Heart Injuries Heart Transplantation Heart failure Human Human Genetics In Vitro Individual Infection Ion Channel Knowledge Laboratories Link Measures Mentored Patient-Oriented Research Career Development Award Mentors Microbiology Modeling Morbidity - disease rate Mutate Mutation Myocarditis Myocardium Odds Ratio Outcome Pathogenesis Patients Pattern Pediatrics Phenotype Play Predisposition Prevalence Preventative vaccination Prognostic Factor Prophylactic treatment Publishing RNA Splicing RNA Viruses Recovery Registries Research Research Personnel Risk Rodent Role Sampling Scientist Severities Severity of illness Silent Mutation Site Source Survivors Technology Text Therapeutic Training Variant Ventricular Viral Virus Virus Diseases Virus Replication Work base biobank career development causal variant clinical decision-making clinical phenotype cohort cytotoxicity exome sequencing experimental study genetic epidemiology genetic risk factor genetic testing genetic variant genome sciences genomic data high risk improved induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inherited cardiomyopathy insight medical schools mouse model mutant next generation sequencing novel pathogen personalized medicine personalized screening proband professor protein degradation response risk stratification screening secondary analysis stem cell model symposium trend viral myocarditis virology

项目摘要

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.

项目概要/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) 西奈山伊坎医学院 (ISMMS) 的一名临床医生。心脏病学科学家，专门研究心血管遗传学。此应用程序的目的是支持博士。康托罗维奇的职业生涯从受指导的研究员转变为以下领域的独立研究员心血管基因组学和心肌炎（AM）是心力衰竭的最常见原因。其他方面健康的儿童，也是成人扩张型心肌病的重要原因。心肌病毒在环境中很常见，但大多数接触者不会出现 AM 和 PI 最近表明，这种可变的反应与那些确实有不同疾病表达的人有关。心肌病遗传变异，这一发现将 AM 的范式转变为人类遗传变异的领域本文的研究策略建议探索影响易感性的遗传因素。以及通过下一代测序 (NGS) 对 650 名 AM 受试者进行的 AM 结果，这是最大的队列具体目标是：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程度之间的关系，3) 使用对照来模拟病毒 AM 和“心肌病”人类诱导多能干细胞衍生的心肌细胞，以研究病毒的影响这种方法利用 NGS 数据、基因组分析和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 AM。K23 奖将通过在四个基本领域进行培训来支持实现这些目标：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 RNA 病毒以及 4) 职业发展计划需要正式的职业发展计划。由主要导师 Bruce Gelb 博士主持的课程、讲习班、研讨会、会议和辅导课程，儿科和遗传学与基因组科学教授，心血管疾病遗传学领域的领导者，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，联合首席导师 Inga Peter 博士是遗传学与基因组科学教授，在以下领域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将构成该研究的结果。 K23 奖励期结束前 R01 申请的基础，该申请将重点关注基于细胞的研究筛选个性化药物疗法、特定“心肌炎基因”的小鼠模型和更大的模型临床研究。