Project 3 - Shah

项目3-基因x应激对疾病前期影响的分子机制 内表型 项目总结 在我们之前的合作工作中，在表型良好的人类中使用了一种集中的遗传方法 队列，我们已经确定了候选基因变异之间的一致关联， “内表型”和疾病终点。然而，调解的途径和机制 我们发现的其他基因关联却知之甚少。发展中的分子技术 现在可以快速、高通量地分析数百万个循环中的基因和其他“基因组” 标记；使用复杂的分析和生物信息学技术，这些“基因组”特征可以 整合以了解潜在的疾病特征的生物途径，重点是遗传 协会、对药物/环境的反应等。因此，在本提案中，我们将整合 来自几个国家的血液样本中的遗传学、代谢组学、转录组和表观遗传学 识别新的生物标志物和分子途径的大型、表型良好的队列 这些关系。我们还将在假设生成方法中使用此方法 将心理社会应激与心血管疾病联系起来的独特表型(即Takosubo‘s心肌病和 精神应激性脑缺血)。我们将通过以下方式实现本项目的目标 具体目标如下：(1)检验候选基因表观遗传变异的假设 从我们之前的工作来看，也会与相同的内表型和疾病相关 终点，并逐渐影响基因在这些表型上的表达； 将表观遗传学、转录组学和代谢组学整合到一个“无偏见”的系统生物学中 方法，目的是阐明调节SNPs之间关联的机制， 来自我们先前工作的内表型和心血管疾病终点；(3)识别遗传和表观遗传学 与心理社会应激与心血管疾病相关的新表型相关的变异。

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.