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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.

项目总结