Regulatory Elements in Dilated Cardiomyopathy

描述(由申请者提供)：这项建议需要一个为期五年的培训计划，重点是为申请者在学术心血管医学领域的独立职业生涯做准备。该项目旨在传授申请者所需的技能和知识，以实现其将基因组洞察带入心血管疾病的长期目标。申请者的直接培训目标是学习更多的测序技术，用更复杂的网络模型分析数据集，并获得更多的工作台经验，以便在Silico发现中进行验证。其他目标包括培养自主运作所需的行政技能，并组成一个工作机构，使其能够作为独立调查员提供资金。在他的长期导师迈克尔·斯奈德和他精心挑选的高级调查顾问委员会的指导下，申请人将拥有实现这些目标和过渡到独立的资源和支持。项目说明心力衰竭影响了近600万美国人。扩张型心肌病(DCM)是心力衰竭患者中最大的一类。遗传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，所有这些患者心脏特有的左心室增大和薄而收缩不良的心肌壁代表着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得到反映。以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了扩张型心肌病组织中胎儿基因的异位表达。然而，对多层表观基因组和转录因子的全球系统研究尚未在人类DCM组织中进行。然而，即使在此之前，关于由调控元件管理转录的规则也才刚刚开始被理解。这项提议寻求在模型细胞系和正常组织中模拟调节组的元件，然后试图了解它们在疾病状态下的变化。最终目标是应用涉及全球调控因素数据的综合分析，以获得对扩张型心肌病疾病过程的新见解，从而发现潜在的治疗新途径。

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.