Gene Transcripts and Proteomics in Families with Platelet Hyperaggregation

血小板过度聚集家族的基因转录和蛋白质组学

• 批准号: 8696113
• 负责人: Lewis C Becker
• 金额: $ 79.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696113
• 关键词: Acute; Adenosine Diphosphate; African American; Agonist; American; Arterial Fatty Streak; Atherosclerosis; Biological; Biology; Blood; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chromosome Mapping; Coagulation Process; Collagen; Coronary heart disease; Development; Epinephrine; Equipment and supply inventories; Ethnic Origin; European; Event; Family; Family Study; Family history of; Family member; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genomics; Goals; Individual; Intercistronic Region; Introns; Ischemia; Lead; Maps; Mass Spectrum Analysis; Mediating; Membrane; Messenger RNA; Methods; Myocardial Infarction; Participant; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Platelet aggregation; Play; Population; Process; Protein Isoforms; Proteins; Proteomics; RNA Splicing; Relative (related person); Risk; Role; Signal Transduction; Staging; Stroke; Structure; Thrombosis; Transcript; Translating; Variant; acute coronary syndrome; artery occlusion; base; caucasian American; design; early onset; family structure; gene discovery; genome wide association study; genome-wide; insight; new therapeutic target; novel strategies; premature; proband; public health relevance; response

DESCRIPTION (provided by applicant): Platelets play a major role in the development of atherothrombotic cardiovascular diseases. Platelet hyperaggregation is an important intermediate phenotype for myocardial infarction, acute coronary syndromes, and strokes. We have discovered and replicated GWAS signals for platelet aggregation in two-generational families of premature coronary disease probands (GeneSTAR), 334 European Americans and 232 African Americans. These families are highly enriched with both platelet hyper-aggregation and incident acute cardiovascular events. Although platelet aggregation is highly heritable, all of the identified GWAS signals together explain only a small fraction of its variance among individuals. In addition, most of the identified GWAS signals are located in introns and intergenic regions, so it is not clear how the variant is functionally related to the aggregation response. In this application we propose to discover new pathways regulating platelet aggregation by determining which genes are expressed in subjects with platelet hyperaggregation. By sequencing the entire platelet transcriptome we will identify changes in the amount or quality (e.g., splice variants) of mRNA transcripts that are associated with specific platelet hyperaggregation phenotypes. Our aims are to: (1) use a unique family-based design to discover the genes that are differentially expressed in white and African American subjects with platelet hyperaggregation compared to control subjects, (2) leverage our prior GWAS to identify eQTLs associated with transcript expression to help prioritize transcripts/genes for further study, and (3) use quantitative mass spectrometry to determine whether changes in gene expression in hyperaggregating platelets are accurately reflected in corresponding changes in expressed proteins. This study will produce a complete quantitative inventory of all mRNA transcripts present in platelets, as well as a complete eQTL map of genetic loci responsible for transcript expression specifically in platelets in both European and African Americans. The inclusion of both ethnicities will allow us to both replicate mRNA findings and amplify biological insights, given the different LD patterns of the two groups. The results will provide new insights into the functional pathways mediating the most important genomic associations with platelet hyperaggregation identified in previous GWAS studies. We expect that our studies will identify previously unknown proteins and biological pathways responsible for platelet hyperaggregation, which may then serve as new therapeutic targets and ultimately more effective and specific approaches for inhibition of platelet function in the large number of people at risk for thrombotic vascular occlusions being treated with anti-platelet therapy.

描述(申请人提供)：血小板在动脉粥样硬化性血栓心血管病的发展中起主要作用。血小板高聚集是心肌梗死、急性冠脉综合征和中风的重要中间表型。我们已经在两代人的早发冠心病先证者家族(GeneSTAR)、334名欧洲裔美国人和232名非洲裔美国人中发现并复制了血小板聚集的Gwas信号。这些家族高度富含血小板超聚集和突发的急性心血管事件。尽管血小板聚集是高度可遗传的，但所有 识别出的Gwas信号一起只解释了它在个体之间的一小部分差异。此外，大多数已鉴定的Gwas信号位于内含子和基因间隔区 区域，因此目前还不清楚该变体在功能上如何与聚合响应相关。在……里面 在这项应用中，我们建议通过确定哪些基因在血小板过度聚集的受试者中表达来发现调节血小板聚集的新途径。通过对整个血小板转录组进行测序，我们将确定与特定的血小板高聚集表型相关的mRNA转录本的数量或质量的变化(例如，剪接变体)。我们的目标是：(1)使用独特的基于家族的设计来发现与对照受试者相比，患有血小板高聚集的白人和非裔美国人受试者中差异表达的基因，(2)利用我们之前的GWAS来识别与转录表达相关的eQTL，以帮助确定转录本/基因的优先顺序，以便进一步研究， 以及(3)使用定量质谱学来确定高聚集血小板中基因表达的变化是否准确地反映在所表达的蛋白质的相应变化中。这项研究将对存在于血小板中的所有mRNA转录本进行完整的定量盘点，以及对欧洲人和非裔美国人的血小板中特定转录物表达负责的遗传位点的完整eQTL图谱。考虑到两组不同的LD模式，这两个种族的纳入将使我们既能复制mRNA的发现，又能放大生物学洞察力。这一结果将为我们提供新的见解，了解在以前的GWAS研究中确定的与血小板过度聚集最重要的基因组关联的功能途径。我们期望我们的研究将确定以前未知的导致血小板过度聚集的蛋白质和生物途径，然后它们可能成为新的治疗靶点，并最终成为更有效和更具体的方法来抑制大量血栓形成风险人群的血小板功能。 血管闭塞正在接受抗血小板治疗。