Genomic and Proteomic Architecture of Atherosclerosis

动脉粥样硬化的基因组和蛋白质组结构

• 批准号: 8513405
• 负责人: DAVID McLeod HERRINGTON
• 金额: $ 217.71万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-18 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513405
• 关键词: Architecture; Arterial Fatty Streak; Arteries; Atherosclerosis; Autopsy; Candidate Disease Gene; Cardiology; Cardiovascular Diseases; Cardiovascular system; Clinical; Communities; Coronary; DNA; Data; Data Set; Databases; Disease; Evaluation; Event; Financial cost; Funding; Gene Proteins; Genes; Genetic; Genetic Markers; Genetic Variation; Genome; Genomics; Genotype; Goals; Human; Human Genome; Individual; Investigation; Knowledge; Lead; Mass Spectrum Analysis; Measures; Meta-Analysis; Methods; Molecular; Molecular Biology; National Heart, Lung, and Blood Institute; Nomenclature; Parents; Pathology; Pathway interactions; Phenotype; Post-Translational Protein Processing; Proteins; Proteome; Proteomics; RNA Splicing; Resources; Risk; Sampling; Scientist; Signal Transduction; Signaling Protein; Specimen; Statistical Methods; Systems Biology; Techniques; Tissue Sample; Tissues; United States National Institutes of Health; Validation; Variant; Youth; base; case control; cohort; early onset; exome; exome sequencing; genetic epidemiology; genetic variant; genome wide association study; insight; multiple reaction monitoring; new therapeutic target; novel; premature; premature atherosclerosis; promoter; public health relevance; repository; screening; tool; trait

DESCRIPTION (provided by applicant): Our goal is to identify variants in the human genome and corresponding changes in the arterial proteome that are correlated with premature atherosclerosis. To accomplish this goal we plan detailed molecular characterization of arterial tissue from subjects in the Pathobiologic Determinants of Atherosclerosis in Youth (PDAY) repository. We will integrate genomic and proteomic data from the PDAY samples and use additional systems biology tools and data from other NIH funded genomic resources to optimize the search for molecular correlates of early disease. Our specific aims are: Aim 1. To identify genetic variants associated with premature atherosclerosis in PDAY, including: a. rare variants in genes identified through PDAY case-control exome and promoter sequencing, and b. common variants identified through a (previously conducted) PDAY GWAS. Nominally significant exome sequencing and GWAS results will be combined with similar sequencing and GWAS data from the ESP Early Onset MI Project (N=2,400) and the MIGen Consortium (N=6,402) using meta- analysis to refine the list of candidate gene products for protein validation. (Aim 3) Aim 2. To expand and prioritize the list of candidate proteins from Aim 1 using statistical methods to combining evidence from SNPs, rare variants and structural variants, gene-pathway enrichment techniques based on a priori knowledge of gene networks (eg. KEGG, Ingenuity, PPI, GO, etc.), and functional evaluation of specific genetic markers using Polyphen-2 and related tools. Aim 3. To measure case-control differences in arterial wall concentration of proteins identified in Aims 1 and 2. For this aim we will exploit the multiplex capability of a new quantitative mass-spectrometry method, multiple reaction monitoring (MRM), to evaluate ~150 arterial wall proteins in all 1,100 PDAY case-control subjects. Aim 4. To further evaluate genetic variants and proteins with the most compelling evidence for association using genotyping, specific protein quantitation and complementary immunohistochemical analyses in de-novo post-mortem arterial specimens from subjects with and without extensive atherosclerosis (N=150). Aim 5. To provide harmonized nomenclature and annotation for the data from Specific Aims 1-4 and share the entire data set with the scientific community through the appropriate publically accessible NCBI databases. This combination of highly specific and precise histopathologic phenotyping with state-of-the-art molecular and analytic methods creates an unprecedented opportunity to construct the genomic and proteomic architecture of premature atherosclerosis and will add fundamentally new knowledge about the linkage between genome and proteome in the artery wall.

描述（由申请人提供）：我们的目标是识别人类基因组中的变异体以及与早产动脉粥样硬化相关的动脉蛋白质组中的相应变化。 为了实现这一目标，我们计划了来自青年（PDAY）储存库中动脉粥样硬化的病理学决定因素的动脉组织的详细分子表征。我们将整合来自pday样品的基因组和蛋白质组学数据，并使用其他NIH资助的基因组资源的其他系统生物学工具以及数据来优化寻找早期疾病的分子相关性的搜索。我们的具体目的是：目标1。确定pday中与早产动脉粥样硬化相关的遗传变异，包括：a。通过pday病例对照外显子组和启动子测序鉴定的基因中的罕见变体以及b。通过（以前进行的）pday GWAS鉴定的常见变体。 名义上显着的外显子组测序和GWAS结果将与ESP早期MI项目（n = 2,400）的类似测序和GWAS数据结合使用，并使用元分析将MIGEN CONSTIUM（n = 6,402）结合使用，以优化用于蛋白质验证的候选基因产品列表。 （目标3）目的2。要使用统计方法来扩展和优先考虑AIM 1的候选蛋白列表，以结合SNP，稀有变体和结构变体的证据，基于基于基因网络的先验知识的基因 - 核心富集技术（例如KEGG。KEGG，Ingenuity，PPI，PPI，GO等）以及使用特定属性标记的工具。 目的3。为了测量目标1和2中鉴定的蛋白质动脉壁浓度的病例对照差异。为了为此，我们将利用一种新的定量质谱法的多重能力，多重反应监测（MRM），以评估〜150个动脉壁蛋白在所有1,100 pday pday病例中。 目的4。用基因分型，特异性蛋白质定量和互补的免疫组织化学分析在DE-NOVO后验尸后动脉标本中，使用基因分型，特异性蛋白质定量和互补的免疫组织化学分析来进一步评估遗传变异和蛋白质的遗传变异和蛋白质。 目标5。为特定目标1-4的数据提供统一的命名法和注释，并通过适当的公开访问的NCBI数据库与科学界共享整个数据集。 高度特异性和精确的组织病理学表型与最先进的分子和分析方法的结合创造了前所未有的机会，可以构建早产动脉粥样硬化的基因组和蛋白质组织结构，并在根本上增加有关动脉壁基因组和蛋白质组之间的链接的基本知识。