Studies on Genetics in Heart Failure

描述（由申请人提供）： 申请人的学术生涯证明了对以患者为导向的研究的长期承诺，在心力衰竭患者外周血管紧张度调节中血管内皮作用研究的广泛专业知识，以及指导研究员从事以患者为导向的研究的成功记录。申请人的职业规划是继续扩大研究兴趣，以心力衰竭的遗传流行病学研究，加强现有的基础和临床研究人员在耶鲁大学形成新的合作关系，并继续为年轻的临床研究人员成功的指导计划。指导计划包括三个关键组成部分：1）在以患者为导向的研究中进行密集的个性化培训; 2）耶鲁大学关于临床试验设计，数据分析，赠款写作和伦理学的教学计划; 3）由以患者为导向的研究专家团队进行批判性审查。在以患者为导向的研究中继续职业中期研究者奖将提供急需的保护时间来实现这些职业目标。耶鲁大学为申请人的职业发展提供了强大的制度环境。耶鲁大学内科和心血管内科承诺保护申请人50%的时间用于以患者为导向的研究和指导。该研究计划的目的是描述遗传因素在非家族性慢性心力衰竭（CHF）中的作用。检测基因的影响，在复杂的性状，如CHF可能有助于通过表征中间表型与定量生理测量相关的功能效应的特定候选基因蛋白质产物。我们建议在健康对照组和CHF患者中前瞻性地确定血管调节基因中常见的DNA变异体与静息状态下肱动脉内皮依赖性血流介导的扩张以及对一过性同型半胱氨酸诱导的氧化应激的反应之间的关系。我们假设，当调整疾病严重程度和其他潜在的混淆临床、生化和饮食因素时，调节一氧化氮、活性氧、同型半胱氨酸和铁代谢的候选基因中的常见DNA变异与血管反应的异质性相关。拟议的研究将促进申请人的职业发展，并提供新的见解CHF的病理生理学。

DESCRIPTION (provided by applicant): The applicant's academic career demonstrates a long-term commitment to patient-oriented research, extensive expertise in the study of the role of the vascular endothelium in the regulation of peripheral vasomotor tone in patients with heart failure, and a successful record in mentoring fellows for careers in patient-oriented research. The career plan of the applicant is to continue expansion of research interests to studies of genetic epidemiology in heart failure, to strengthen existing and form new collaborative relationships with basic and clinical investigators at Yale, and to continue the successful mentoring program for young clinical investigators. The mentoring program consists of three key components: 1) intensive individualized training in patient-oriented research; 2) Yale University didactic programs on clinical trial design, data analysis, grant writing, and ethics; 3) critical review by a team of patient-oriented research experts. Continuation of the Midcareer Investigator Award in Patient-Oriented Research will provide critically needed protected time to achieve these career goals. Yale provides a strong institutional environment for support of the applicant's career development. The Department of Internal Medicine and Section of Cardiovascular Medicine at Yale have committed to protect 50% of the applicant's time for patient-oriented research and mentoring. The aim of the research plan is to characterize the role of genetic factors in non-familial chronic heart failure (CHF). Detection of gene effects in complex traits like CHF may be facilitated by characterization of intermediate phenotypes with quantitative physiological measurements relevant to the functional effects of specific candidate gene protein products. We propose to prospectively determine the relationship between common DNA variants in vascular regulatory genes and endothelium-dependent flow-mediated dilation of the brachial artery at rest and in response to transient homocysteine-induced oxidative stress in healthy control subjects and subjects with CHF. We hypothesize that common DNA variants in candidate genes that regulate metabolism of nitric oxide, reactive oxygen species, homocysteine and iron are associated with heterogeneity of vascular responses when adjusted for disease severity and other potential confounding clinical, biochemical and dietary factors. The proposed studies will advance applicant career development and provide new insight into pathophysiology of CHF.