Regulatory Elements in Dilated Cardiomyopathy

描述（由申请人提供）：该提案需要一个为期五年的培训计划，重点是准备申请人在学术心血管医学的独立职业生涯。该项目旨在传授申请人所需的技能和知识，以实现将基因组学见解引入心血管疾病的长期目标。申请人的直接培训目标是学习更多的测序技术，使用更复杂的网络模型分析数据集，并获得进一步的实验室经验以验证计算机结果。其他目标包括发展自主运作所需的行政技能，并完成一系列工作，使独立调查员能够获得资金。在他的长期导师Michael Snyder和他精心挑选的高级调查员咨询委员会的指导下，申请人将拥有实现这些目标并向独立过渡的资源和支持。心力衰竭影响着近600万美国人。扩张型心肌病（DCM）是收缩性心力衰竭中最大的一类。遗传学被认为只在少数病例中起作用;然而，无论是什么原因，包括遗传学，所有这些患者的心脏所特有的扩大的左心室和薄的、收缩不良的心肌壁代表了最终共同途径的结果。这种结构重塑通过基因转录的变化在分子水平上反映出来。先前在小鼠系统中的工作已经表明，影响染色质可及性的分子参与导致扩张型心肌病组织中胎儿基因的异位表达。然而，尚未对人类DCM组织进行多层表观基因组和转录因子的全球性、系统性研究。然而，即使在此之前，关于调控元件对转录的管理的规则才刚刚开始被理解。该提案试图在试图了解疾病状态下的改变之前，在模型细胞系和正常组织中模拟调节组的元素。最终目标是应用涉及全球调控元素数据的集成分析，以获得DCM疾病过程的新见解，从而发现潜在的新治疗途径。

DESCRIPTION (provided by applicant): This proposal entails a five-year training program focused on preparing the applicant for an independent career in academic cardiovascular medicine. This project aims to impart the skills and knowledge required for the applicant to achieve his long-term goal of bringing genomic insights into cardiovascular disease. The immediate training objectives of the applicant are to learn more sequencing techniques, to analyze datasets with more sophisticated network models, and to acquire further bench experience to validate in silico findings. Other objectives include developing administrative skill required to function autonomously and composing a body of work that will enable funding as an independent investigator. Under the guidance of his long-term mentor Michael Snyder and his carefully selected advisory committee of senior investigators, the applicant will have the resources and support to achieve these goals and transition to independence. Project Description Heart failure affects nearly six million Americans. Dilated cardiomyopathy (DCM) represents the largest class among those with systolic heart failure. Genetics is thought to play a role in only a minority of cases; yet, whatever the cause, including genetic, the enlarged left ventricles and thin, poorly contracting myocardial walls characteristic of the hearts of all these patients represent the outcome of a final common pathway. This structural remodeling is reflected on the molecular level by changes in the transcription of genes. Already, previous work in a murine system has shown the involvement of molecules affecting chromatin accessibility leading to the ectopic expression of fetal genes in dilated cardiomyopathy tissue. However, a global, systematic study of multiple layers of the epigenome and transcription factors has yet to be performed on human DCM tissues. Even before that, though, the rules regarding the governance of transcription by regulatory elements is only beginning to be understood. This proposal seeks to model elements of the regulome in model cell lines and normal tissues before trying to understand their alterations in diseased states. The ultimate goal is to apply integrativ analysis involving global, regulatory element data to gain new insights in the disease process of DCM and thereby uncover potential new avenues for therapeutics.