Functional genomics investigation of pleiotropic vascular disease loci

多效性血管疾病位点的功能基因组学研究

基本信息

批准号：
10501722
负责人：
Clint L Miller
金额：
$ 58.63万
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：
2022-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10501722
关键词：
Actins Adopted Affect Architecture Arteries Atherosclerosis Binding Binding Sites Biological Markers Blood Blood Vessels Candidate Disease Gene Cell physiology Cells Cerebrum Cervical Chromatin Clinical Complex Coronary Coronary Arteriosclerosis Coronary artery Cytoskeleton Data Data Set Deposition Development Disease Disease Outcome Early treatment Endothelial Cells Environmental Risk Factor Event Extracellular Matrix Fibroblasts Functional disorder Gap Junctions Gene Structure Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Transcription Genomics Heterogeneity Human Image Immune In Situ Injury Intervention Studies Investigation Knowledge LIM Domain LIM Domain Protein Label Lead Lipids Maps Measures Mediating Meta-Analysis Mission Mus Muscle Muscle Contraction Myocardial Infarction Osteoblasts Pathologic Pathway interactions Pericytes Phenotype Physiological Play Population Prevalence Prevention strategy Preventive measure Process Protein Family Proteins Proteomics Public Health Quantitative Trait Loci RNA Regulation Regulator Genes Regulatory Pathway Research Risk Risk Factors Role Smooth Muscle Myocytes Stroke Supporting Cell System Testing Therapeutic Tissues Translating United States National Institutes of Health Validation Variant Vascular Diseases Work advanced disease arterial remodeling arterial stiffness base calcification causal variant clinically relevant cofactor coronary artery calcification coronary lesion disease phenotype disorder risk epigenomics functional genomics gene regulatory network genetic association genetic variant genome wide association study genome-wide genomic locus human disease improved insight knock-down multiple omics novel overexpression patient stratification programs response risk variant single cell analysis single cell sequencing three dimensional cell culture trait transcription factor transcriptome transcriptome sequencing treatment strategy

项目摘要

PROJECT SUMMARY Complex vascular diseases such as coronary artery disease (CAD), myocardial infarction (MI), and coronary artery calcification (CAC) pose considerable public health burden worldwide and involve both genetic and environmental risk factors over a lifetime. Given the rising prevalence of vascular diseases across human populations, there is an urgent need for new treatments and preventative measures that target the primary disease processes in the vessel wall. Genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with vascular disease risk. Large-scale functional genomic studies have begun to resolve many of the causal genes, variants, and pathways at these loci and demonstrated shared genetic etiologies. However, it still remains a challenge to translate these genetic discoveries into biologically and clinically relevant insights. More than half of the CAD/MI loci are associated independently of classical risk factors and may point to vascular dysfunction. Our group and others have adopted a systems-based approach to prioritize the genes and mechanisms altered by disease risk loci in human coronary artery smooth muscle cells (SMC). SMC normally regulate vascular tone but play critical roles in atherosclerosis as their contractile gene program is hijacked during phenotypic switching to immune cell, fibroblast-like, and osteoblast-like cells. Using multi-omics and quantitative trait locus mapping in human coronary artery SMC and tissues we recently identified candidate causal genes and mechanisms for CAD-related vascular dysfunction. Single-cell analyses of human coronary lesions demonstrated a critical role for CAD-associated transcription factors (e.g. TCF21) in regulating SMC phenotypic switching during atherosclerosis. Using single-cell epigenomic profiling of coronary arteries (n=41) we also identified novel SMC specific transcriptional regulators that are associated with multiple vascular diseases. Integrative fine-mapping analyses prioritized Four-and-a-Half LIM domains 5 (FHL5) as a causal gene for CAD/MI and subclinical vascular diseases. Interestingly, FHL5 overexpression decreased SMC contractility, and increased proliferation and calcification, consistent with the genetic association for CAC. Finally, FHL5 chromatin and transcriptome profiling in SMC support its role as a transcriptional cofactor, by altering SMC contractility and extracellular matrix expression/regulation. These data suggest that elucidating its trans-regulatory pathways may resolve mechanisms of pleiotropic risk across these conditions. Herein, we plan to perform functional genomic studies of FHL5 in both human vascular cells and arteries ex vivo to determine its role in vascular dysfunction, through altered actin cytoskeleton and extracellular matrix regulation, and vasoreactivity. We will further reveal its target binding regions, protein interactomes, and construct multi-omic gene regulatory networks to determine the effects of the FHL5 regulome on subclinical and advanced disease outcomes. Together these studies will reveal key regulatory cascades and biomarkers for multiple vascular conditions and inform novel early treatment or prevention strategies to eradicate these debilitating diseases.

项目概要复杂的血管疾病，如冠状动脉疾病（CAD）、心肌梗塞（MI）和冠状动脉疾病动脉钙化（CAC）在全世界范围内造成相当大的公共卫生负担，涉及遗传和一生中的环境风险因素。鉴于人类血管疾病的患病率不断上升人群，迫切需要针对主要疾病的新治疗方法和预防措施血管壁的疾病过程。全基因组关联研究（GWAS）已经确定了数百个与血管疾病风险相关的遗传位点。大规模的功能基因组研究已经开始解决了这些基因座上的许多因果基因、变异和途径，并证明了共享遗传病因学。然而，将这些遗传发现转化为生物学和生物学上的发现仍然是一个挑战。临床相关的见解。超过一半的 CAD/MI 基因座与经典风险无关因素，并可能表明血管功能障碍。我们的团队和其他人采用了基于系统的方法优先考虑人类冠状动脉平滑肌中疾病风险位点改变的基因和机制细胞（SMC）。 SMC 通常调节血管张力，但由于其收缩性，在动脉粥样硬化中发挥着关键作用基因程序在表型转换为免疫细胞、成纤维细胞样和成骨细胞样细胞的过程中被劫持。最近，我们利用人类冠状动脉 SMC 和组织中的多组学和数量性状基因座作图确定了 CAD 相关血管功能障碍的候选致病基因和机制。单细胞分析人类冠状动脉病变的研究表明 CAD 相关转录因子（例如 TCF21）在调节动脉粥样硬化期间 SMC 表型转换。使用冠状动脉的单细胞表观基因组分析动脉 (n=41) 我们还发现了与多种相关的新型 SMC 特异性转录调节因子血管疾病。综合精细映射分析优先考虑四个半 LIM 域 5 (FHL5) 作为 CAD/MI 和亚临床血管疾病的致病基因。有趣的是，FHL5 过度表达减少 SMC 收缩性、增殖和钙化增加，与 CAC 的遗传关联一致。最后，SMC 中的 FHL5 染色质和转录组分析支持其作为转录辅助因子的作用：改变 SMC 收缩性和细胞外基质表达/调节。这些数据表明，阐明其跨监管途径可能会解决这些条件下的多效性风险机制。在此，我们计划在离体人类血管细胞和动脉中进行 FHL5 的功能基因组研究，以确定通过改变肌动蛋白细胞骨架和细胞外基质调节，其在血管功能障碍中的作用，以及血管反应性。我们将进一步揭示其靶结合区域、蛋白质相互作用组，并构建多组学基因调控网络以确定 FHL5 调控组对亚临床和晚期疾病的影响结果。这些研究将共同揭示多种血管的关键调控级联和生物标志物并提供新的早期治疗或预防策略以根除这些使人衰弱的疾病。