GENOMICS OF CARDIOVASCULAR DEVELOPMENT, ADAPTION

这种PGA的目标是开始将基因与功能、功能障碍和 因临床原因引起的心血管系统结构异常 相关、遗传和环境刺激。主要的生物学主题 需要研究的是心血管系统的转录网络是如何 对遗传和环境压力做出反应，以维持正常的功能和 结构，以及这个网络在疾病中是如何改变的。在具体目标1中， 调查人员将采取多学科方法，结合定义明确的 心肌病和血管病小鼠模型的综合分析 生理学、病理学和RNA表达谱分析以寻找原型 不同遗传性和非遗传性反应的基因表达模式 微扰。在具体目标2中，调查人员将执行 利用获得的人心肌和血管组织进行转录图谱分析 在心脏移植或活组织检查时，比较转录 配置文件数据与各种鼠标型号的数据。在具体目标3中， 研究人员将筛查导致心血管疾病的突变 特别强调肥厚型心肌病的扩张型畸形 心肌病，以及精选的先天性心脏病患者。 在特定目标4中，研究人员将检查200个候选基因， 由老鼠和人类的表达研究确定，在2093个人 摘自弗雷明翰心脏研究。在这些研究中，单个核苷酸 DNA多态分析(SNP)将与超声心动图相关 左心室质量、心功能、心腔大小的证据 和主动脉根部大小。上述所有研究所产生的数据将是 通过最新的信息学分析来搜索常见AS的逻辑 以及疾病特有的途径。这些数据将经过广泛的注释和 通过互动方式向科学界免费提供 网站。总而言之，这次PGA将产生高质量的、全面的 结构和功能适应的功能基因组学数据集 通过整合来自动物模型的表达数据来研究心血管系统 和人体组织样本，患者候选基因的突变筛查， 以及在特征良好的普通人群中的DNA多态。这样的数据 SET将成为未来基础、临床和药物基因组学的基准 学习。

The goal of this PGA is to begin linking genes to function, dysfunction and structural abnormalities of the cardiovascular system caused by clinically relevant, genetic and environmental stimuli. The principal biological theme to be pursued is how the transcriptional network of the cardiovascular system responds to genetic and environmental stresses to maintain normal function and structure, and how this network is altered in disease. In Specific Aim 1, the investigators will take a multidisciplinary approach combining well-defined mouse models of cardiomyopathy and vasculopathy with an integrated analysis of physiology, pathology, and RNA expression profiling to search for prototypical patterns of gene expression in response to various genetic and non-genetic perturbations. In Specific Aim 2, the investigators will perform transcriptional profiling using human myocardium and vascular tissues obtained at the time of cardiac transplant or biopsy, and compare the transcriptional profile data with those of various mouse models. In Specific Aim 3, the investigators will screen for mutations that cause cardiovascular malformations with particular emphasis on hypertrophic cardiomyopathy, dilated cardiomyopathy, and selected sets of patients with congenital heart disease. In Specific Aim 4, the investigators will examine 200 candidate genes, identified by the mouse and human expression studies, in 2093 individuals drawn from the Framingham Heart Study. In these studies, a single nucleotide DNA polymorphism analysis (SNP) will be correlated with echocardiographic evidence of left ventricle mass, ventricular function, cardiac chamber size and aortic root size. The data generated by all of the above studies will be analyzed by state-of-the-art informatics to search for logics for common as well as disease specific pathways. The data will be extensively annotated and made freely available to the scientific community through the interactive website. In summary, this PGA will generate a high quality, comprehensive data set for the functional genomics of structural and functional adaptation of the cardiovascular system by integrating expression data from animal models and human tissue samples, mutation screening of candidate genes in patients, and DNA polymorphisms in a well characterized general population. Such a data set will serve as a benchmark for future basic, clinical and pharmacogenomic studies.