Systems Genetics of Vascular Smooth Muscle Phenotypes

血管平滑肌表型的系统遗传学

基本信息

批准号：
10559249
负责人：
Mete Civelek
金额：
$ 50.74万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559249
关键词：
ARVCF gene Affect African ancestry Allelic Imbalance Antihypertensive Agents Aorta Arterial Fatty Streak Arteries Asian ancestry Atherosclerosis Bayesian Network Biological Biological Assay Blood Vessels Cause of Death Cell Culture Techniques Cell Separation Cell physiology Characteristics Cholesterol Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Complex Computational Biology Coronary Coronary Arteriosclerosis Coronary artery Data Diagnosis Disease Disease susceptibility Donor person Early Diagnosis Enhancers Environmental Risk Factor European ancestry Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genetic Variation Genetic study Genome Genotype Goals Heart Transplantation Human Human Resources Immunohistochemistry In Vitro Individual Inflammatory Latinx Lentivirus Linkage Disequilibrium Lipids Maps Measures Modeling Molecular Myocardial Infarction Pathway interactions Pharmaceutical Preparations Phenotype Play Process Proliferating Protein Analysis Proteins Quantitative Trait Loci RNA Regulation Regulator Genes Regulatory Element Reporter Research Resources Risk Risk Factors Role Series Serum Single Nucleotide Polymorphism Smooth Muscle Myocytes Specimen Stimulus Sudden Death System Testing Time Transcript Translating Transposase United States Untranslated RNA Update Variant Vascular Smooth Muscle Western World ascending aorta calcification causal variant cell type chromatin remodeling clinical care cytokine disorder prevention disorder risk drug discovery experimental study gain of function gene function gene interaction gene network gene regulatory network genetic approach genetic variant genome wide association study genomic locus loss of function migration multi-ethnic particle public health relevance response transcription factor transcriptome sequencing transdifferentiation

项目摘要

PROJECT SUMMARY Coronary artery disease (CAD) remains the leading cause of death in the Western world despite significant advances in early detection and extensive use of lipid-lowering and anti-hypertensive drugs. To date, no single drug has been developed to target the primary disease process in the vessel wall. A complete understanding of the disease susceptibility is urgently needed to develop additional therapies. Common forms of atherosclerosis involve environmental factors, hundreds of genetic variations, and their interactions, each of which exert a relatively small effect on disease susceptibility. The most recent genome-wide association study (GWAS) in nearly six hundred fifty thousand individuals identified 175 independent variants associated with increased risk for CAD. However, most of the underlying genes and the related mechanisms of how these variants contribute to the disease process remain unknown. This proposal outlines an integrative genetics study in a unique resource of human aortic smooth muscle cells (SMCs) isolated from 151 genotyped multi- ethnic heart transplant donors to discover the CAD-associated variants that perturb SMC gene expression and their downstream functional consequences. In recent studies, we measured gene expression in quiescent and proliferative culture conditions representing the transdifferentiation of SMCs from a healthy to an atherogenic phenotype. We identified 84 genes whose expression was associated with CAD variants in GWAS loci. However, the causal genetic variants in these loci remain to be elucidated. Therefore, as part of the proposed studies, we will first perform massively parallel reporter assays to identify the variants that modulate gene expression in SMCs. We will also take advantage of the natural variation in gene expression to construct co- expression and Bayesian networks to understand how the predicted candidate causal genes function in SMCs. We will refine these networks by mapping regulatory elements to nascent RNA transcripts in response to pro- inflammatory cytokines. We will then validate our predictions in gain and loss-of-function experiments in cultured SMCs. We will also validate our predictions in well-phenotyped coronary artery specimens from cases of unexpected sudden death by performing immunohistochemical analysis of proteins encoded by genes that are predicted to play a key role in atherosclerosis-relevant SMC phenotypes. The overall goal of the proposed studies is to integrate systems genetics and computational biology leading to mechanistic predictions of the gene networks that are perturbed by CAD. Besides understanding CAD loci, these integrative genetics studies will provide a useful window into the flow of biological information from genetic variants to SMC gene expression and atherosclerosis-relevant phenotypes.

项目概要尽管冠状动脉疾病（CAD）在西方世界中仍然是导致死亡的主要原因早期检测和广泛使用降脂和抗高血压药物方面取得的进展。迄今为止，还没有一个已开发出针对血管壁原发疾病过程的药物。完整的了解迫切需要了解疾病的易感性以开发其他疗法。常见形式有动脉粥样硬化涉及环境因素、数百种遗传变异及其相互作用，对疾病易感性影响相对较小。最新的全基因组关联研究（GWAS）在近 65 万名个体中发现了 175 个与 CAD 风险增加。然而，大多数潜在基因以及这些基因的相关机制变异对疾病过程的影响仍然未知。该提案概述了综合遗传学对从 151 个基因型多细胞中分离出的独特人类主动脉平滑肌细胞 (SMC) 资源进行的研究种族心脏移植捐献者发现扰乱 SMC 基因表达的 CAD 相关变异，它们的下游功能后果。在最近的研究中，我们测量了静态和静态状态下的基因表达代表 SMC 从健康细胞转分化为致动脉粥样硬化细胞的增殖培养条件表型。我们鉴定了 84 个基因，其表达与 GWAS 基因座中的 CAD 变异相关。然而，这些位点的因果遗传变异仍有待阐明。因此，作为提议的一部分研究中，我们将首先进行大规模并行报告分析，以确定调节基因的变异 SMC 中的表达。我们还将利用基因表达的自然变异来构建共表达和贝叶斯网络来了解预测的候选因果基因如何在 SMC 中发挥作用。我们将通过将调控元件映射到新生 RNA 转录本来完善这些网络，以响应亲炎症细胞因子。然后，我们将在功能增益和功能丧失实验中验证我们的预测培养的 SMC。我们还将在病例中表型良好的冠状动脉标本中验证我们的预测通过对基因编码的蛋白质进行免疫组织化学分析来发现意外猝死预计在动脉粥样硬化相关的 SMC 表型中发挥关键作用。拟议的总体目标研究旨在整合系统遗传学和计算生物学，从而对受 CAD 干扰的基因网络。除了了解 CAD 基因座之外，这些综合遗传学研究将为了解从遗传变异到 SMC 基因的生物信息流提供一个有用的窗口表达和动脉粥样硬化相关表型。