The Genetic Basis of Atrial Fibrillation

心房颤动的遗传基础

• 批准号: 7195810
• 负责人: Dawood Darbar
• 金额: $ 14.91万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195810
• 关键词: Affect; Age of Onset; American; Architecture; Area; Arrhythmia; Atrial Fibrillation; Candidate Disease Gene; Cardiac; Cardiology; Cardiomyopathies; Cardiovascular system; Chromosomes; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 11; Clinic; Clinical; Clinical Investigator; Clinical Pharmacology; Collaborations; Complement; Condition; Coupled; Data; Development; Disease; Elderly; Electrophysiology (science); Environment; Extended Family; Family; Family history of; First Degree Relative; Genes; Genetic; Genetic Heterogeneity; Genetic Medicine; Genetic Predisposition to Disease; Genetic Research; Genetics and Medicine; Genotype; Goals; Heart Diseases; Heart Rate; Heterogeneity; Human; Human Genetics; Hypertension; Hyperthyroidism; Individual; Inherited; Investigation; Laboratory Research; Lead; Life; Location; Long QT Syndrome; Maintenance; Maps; Mentored Clinical Oncology Award; Mentored Clinical Scientist Award; Mentored Patient-Oriented Research Career Development Award; Mentors; Minority; Molecular; Molecular Genetics; Molecular Medicine; Morbidity - disease rate; Mutation; Myocardial; Pathogenesis; Pathway interactions; Patients; Penetrance; Pharmacology; Phenotype; Physiological; Play; Prevention; Prevention strategy; Process; Publishing; Reporting; Research; Research Training; Resources; Role; Secondary to; Sinus; Therapeutic Embolization; Training; Universities; Work; autosomal dominant trait; base; career; early onset; experience; gain of function mutation; genetic analysis; genetic linkage; genome wide association study; improved; insight; kindred; member; middle age; mortality; novel therapeutics; patient oriented research; positional cloning; proband; programs; response; restoration

DESCRIPTION (provided by applicant): The candidate is board certified in Cardiology and Cardiac Electrophysiology. He has an extensive background in cardiovascular research including a Doctorate in Pharmacology. He proposes to use his very strong background in Clinical Pharmacology and Clinical Electrophysiology to develop a program to elucidate the molecular basis of atrial fibrillation (AF). Abundant data from Darbar and others supports the underlying hypothesis that genetic factors play a prominent role in the development of AF and its response to therapy. The resources for the candidate to develop as a clinical investigator and to attack this hypothesis are in place. Through this K23 award, the candidate seeks to obtain formal training in human molecular genetics, while developing a vigorous research program combining patient-oriented research and laboratory-based studies. The highly supportive environment at Vanderbilt University coupled to a formal mentoring process, makes it likely the candidate will develop as a nationally and internationally recognized expert in this area. AF, the most common sustained arrhythmia, affects over 2 million Americans and is associated with significant morbidity and mortality. Current therapies for AF are limited partly due to poor understanding of fundamental mechanisms in disease pathogenesis. Identification of gene(s) responsible for AF will provide important insight into the molecular pathways that contribute to AF. There is growing recognition that AF can be a heritable disorder with loci mapped to chromosomes 10 and 6 and an AF-causing mutation in KCNQ1 gene. The candidate has identified multiple extended families with familial AF. The first aim of this study is to identify and phenotype kindreds with familial AF. The second aim is to genotype families with known/candidate AF genes. Most AF is considered secondary to other conditions such as hypertension, hyperthyroidism, cardiomyopathy or valvular disease; however, a substantial minority of patients without obvious cause are said to have "lone" AF. Preliminary data from Darbar suggest that patients presenting with lone AF in the 4/5 th decades of life have a genetic basis for their condition. Hence, the third aim of this study is investigate the role of genetic factors in patients and their first degree relatives with lone AF while identifying larger kindreds suitable for positional cloning approaches. With this approach, the candidate has identified over 90 probands with lone AF including multiple extended families. This complementary strategy of evaluating individuals and families will enhance our understanding of the molecular pathways of AF and identify novel therapeutic strategies for the prevention and treatment of this common and morbid condition.

描述（由申请人提供）： 该候选人获得了心脏病学和心脏电生理学的董事会认证。他在心血管研究中具有广泛的背景，包括药理学博士学位。他建议在临床药理学和临床电生理学上使用他非常强大的背景来制定一项程序，以阐明房颤的分子基础（AF）。 Darbar和其他人的大量数据支持了基本的假设，即遗传因素在AF的发展及其对治疗的反应中起着重要作用。候选人作为临床研究者发展并攻击这一假设的资源已经到位。通过这一K23奖，候选人试图获得人类分子遗传学的正式培训，同时开发了一个结合了以患者为导向的研究和基于实验室的研究的剧烈研究计划。范德比尔特大学（Vanderbilt University）的高度支持环境加上正式的指导过程，使候选人很可能会发展成为该领域的国家和国际认可的专家。 AF是最常见的持续性心律失常，会影响超过200万美国人，并且与大量发病率和死亡率有关。当前对AF的疗法受到限制，部分原因是对疾病发病机理中基本机制的了解不足。负责AF的基因的鉴定将为有助于AF的分子途径提供重要的见解。人们越来越认识到，AF可能是一种可遗传的疾病，其位点映射到染色体10和6，并且在KCNQ1基因中引起AF的突变。候选人已经确定了多个具有家庭AF的大家庭。这项研究的第一个目的是识别和表型与家族性AF。第二个目的是具有已知/候选AF基因的基因型家族。大多数AF被认为是其他疾病，例如高血压，甲状腺功能亢进，心肌病或瓣膜疾病。但是，据说没有明显原因的少数患者具有“孤独” AF。来自Darbar的初步数据表明，在生命的第4/5年中，出现孤立的患者具有遗传基础。因此，这项研究的第三个目的是研究遗传因素在患者及其一级亲戚中的作用，同时识别适合位置克隆方法的较大属性。通过这种方法，候选人已经确定了90多个唯一的AF，包括多个大家庭。评估个人和家庭的这种补充策略将增强我们对AF分子途径的理解，并确定预防和治疗这种常见和病态状况的新型治疗策略。