Project 3 - Shah

项目3-沙阿

• 批准号: 9277506
• 负责人: Svati H. Shah
• 金额: $ 48.54万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9277506
• 关键词: Alleles; Amino Acids; Back; Bioinformatics; Biological; Biological Markers; Biological Models; Biology; Blood specimen; Candidate Disease Gene; Cardiomyopathies; Cardiovascular Diseases; Cessation of life; Chronic stress; Clinical; Data; Diagnosis; Disease; Distress; Disulfides; Environment; Epigenetic Process; Evaluation; Event; Gene Expression; Genes; Genetic; Genetic Translation; Goals; Heterogeneity; Human; Individual; Intervention; Ischemia; Link; Lipids; Measures; Mediating; Metabolic; Methylation; Molecular; Myocardial Infarction; Obesity; Overweight; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Preventive measure; Proteins; Psyche structure; Psychosocial Factor; Psychosocial Stress; Race; Regulation; Risk; Risk Factors; Risk stratification; Single Nucleotide Polymorphism; Statistical Data Interpretation; Stress; Systems Biology; Techniques; Technology; Testing; Therapeutic Intervention; Validation; Variant; Work; base; behavioral pharmacology; biobehavior; cohort; endophenotype; environmental stressor; epigenetic marker; epigenetic variation; exome sequencing; genetic approach; genetic association; hypothalamic-pituitary-adrenal axis; metabolomics; minimal risk; novel; novel marker; programs; psychosocial; public health relevance; research clinical testing; response; sex; trait; transcriptomics; whole genome

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.

项目3-基因x应力对预性疾病的分子机制 内型型 项目摘要 在我们先前的合作工作中，在良好的人类中使用重点的遗传方法 队列，我们​​已经确定了候选基因变体之间的一致关联， “内型型”和疾病终点。但是，介导的途径和机制 我们确定的其他遗传关联知之甚少。不断发展的分子技术 现在，可以快速，高通量分析数百万循环遗传和其他“ Omic” 标记；使用复杂的分析和生物信息学技术，这些“ OMIC”概况可以是 集成以了解疾病特征的生物学途径，重点为通用 协会，对药物/环境的反应等，在此提案中，我们将整合 遗传学，代谢组学，转录组学和表观遗传学在几种血液样本中构图 大型，良好的类型队列，以鉴定新型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 将社会心理压力与CVD联系起来的独特表型（即Takosubo的心肌病和 精神压力引起的缺血）。我们将通过 以下特定目的：（1）检验候选基因表观遗传变异的假设 从我们先前的工作中，还将与相同的内型和疾病有关 终点，并逐渐影响基因对这些表型的表达； （2）至 “公正”系统生物学中的综合表观遗传学，转录组学和代谢组学 方法，目的是阐明介导SNP之间关联的机制 我们先前的工作中的openophenotypes和CVD端点； （3）鉴定遗传和表观遗传 与新表型相关的变体将社会心理应激与CVD联系起来。