Project 3 - Shah

项目3 -X基因应激对疾病前期影响的分子机制 内表型 项目摘要 在我们之前的合作工作中，使用集中的遗传方法在表型良好的人类中， 队列中，我们已经确定了候选基因中变异之间的一致关联， “内表型”和疾病终点。然而，介导的途径和机制 我们对其他已确定的遗传关联知之甚少。不断发展的分子技术 现在能够快速、高通量地分析数百万个循环的遗传和其他“组学” 标记;使用复杂的分析和生物信息学技术，这些“组学”概况可以 整合以了解疾病特征的生物学途径，重点关注遗传 协会，对药物/环境的反应等。因此，在本提案中，我们将整合 遗传学、代谢组学、转录组学和表观遗传学在来自几个 大的，良好的表型队列，以确定新的生物标志物和分子途径介导 这些关系。我们还将在假设生成方法中使用这种方法， 将心理社会压力与CVD联系起来的独特表型（即Takosubo心肌病和 精神应激诱发的局部缺血）。我们将通过以下方式实现本项目的目标： 以下具体目的：（1）检验候选基因中的表观遗传变异 也将与相同的内在表型和疾病相关 终点，并递增地影响基因在那些表型上的表达;（2） 将表观遗传学、转录组学和代谢组学纳入“无偏见”系统生物学 方法，目的是阐明介导SNP之间关联的机制， 内源性表型和CVD终点从我们以前的工作;（3）以确定遗传和表观遗传 与新的表型相关的变异将心理社会压力与CVD联系起来。

PROJECT 3 - Molecular mechanisms of gene x stress effects on pre-disease endophenotypes PROJECT SUMMARY In our prior collaborative work, using a focused genetic approach in well-phenotyped human cohorts, we have identified consistent associations between variants in candidate genes, “endophenotypes”, and disease endpoints. However, the pathways and mechanisms mediating our other identified genetic associations are poorly understood. Evolving molecular technologies now enable rapid, high-throughput profiling of millions of circulating genetic and other ‘omic’ markers; using sophisticated analytic and bioinformatics techniques, these ‘omic’ profiles can be integrated to understand biological pathways underlying disease traits, focused genetic associations, response to medications/environment, etc. Thus, in this proposal, we will integrate genetics, metabolomics, transcriptomics, and epigenetics profiled in blood samples from several large, well-phenotyped cohorts to identify novel biomarkers and molecular pathways mediating these relationships. We will also use this approach in a hypothesis generating approach for unique phenotypes that link psychosocial stress with CVD (i.e. Takosubo’s cardiomyopathy and mental stress induced ischemia). We will accomplish our goals for this Project through the following Specific Aims: (1) to test the hypothesis that epigenetic variation in candidate genes from our prior work, will also be associated with the same endophenotypes and disease endpoints, and incrementally influence expression of the gene on those phenotypes; (2) to integrate epigenetics, transcriptomics and metabolomics in an “unbiased” systems biology approach, with the goal of elucidating mechanisms mediating the associations between SNPs, endophenotypes and CVD endpoints from our prior work; (3) to identify genetic and epigenetic variants associated with novel phenotypes linking psychosocial stress with CVD.