LncRNA Transcriptional Mechanisms of Coronary Artery Disease Risk

冠状动脉疾病风险的 LncRNA 转录机制

基本信息

  • 批准号:
    10327641
  • 负责人:
  • 金额:
    $ 39.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-01-18 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Therapeutic risk factor modification has provided a significant decrease in coronary artery disease (CAD) in Western populations, however, significant risk is due to common inherited genetic variation that affects disease pathways in the vessel wall and remains poorly understood without specific therapies. To further our long-term goal of characterizing the molecular basis for this genetic risk, we have participated in genome-wide association studies (GWAS) identifying allelic variation linked to coronary artery disease (CAD) risk, and these efforts have yielded hundreds of associated loci. However, the majority of identified causal variation resides outside of protein coding exons, in regulatory regions of the genome that are poorly understood, and further efforts are required to understand the mechanisms of association and thus disease risk. Our central hypothesis is that an important subset of disease allelic variation primarily regulates long non-coding RNA (lncRNA) expression, with this effect modulating causal protein coding gene (pcGene) expression through functional genomic interactions such as chromosomal looping. Our objective here is to investigate the role these lncRNAs play in mediating expression of CAD causal pcGenes, and the mechanism by which they accomplish this function. Our rationale is that lncRNAs serve as a critical intermediary between genetic and epigenetic signaling, and that elucidating their mechanism of function is a key aspect of understanding CAD risk. To gain fundamental information regarding the mode of action of these molecules in the context of CAD, we propose to study human coronary artery smooth muscle cell (HCASMC) lncRNAs. In Aim 1, we will identify lncRNAs regulated in these cells by disease-related stimuli and that map to CAD GWAS loci. Co-expression network analyses will connect these lncRNAs to pcGenes, and initiate network and pathway analyses to begin to establish their biological functional associations. In Aim 2, we will map expression quantitative trait loci variants (eQTLs) for each of the lncRNAs, using a high-throughput allele-specific expression method that provides quantification of low abundance RNAs. Discovered lncRNA eQTLs will be investigated to determine whether they colocalize with CAD GWAS causal variation, as well as genomic molecular trait QTLs. CRISPR genome editing will be employed to validate the eQTLs, and confirm pcGene identity. In Aim 3, we will employ CRISPR inhibition and single cell RNA sequencing (PerturbSeq) to map the transcriptional networks regulated by the disease related lncRNAs, and also investigate their in vitro cellular effects on HCASMC. These studies will be aided by our extensive work with primary cultured HCASMC characterizing epigenome modification, chromatin accessibility, and looping, and our efforts to map CAD GWAS causal variants and genes that mediate risk in this cell type. This work is highly innovative in that it combines unique genomic datasets developed in a highly disease relevant cell type and significant since it will integrate lncRNAs, their regulatory variation, and molecular mechanisms into the etiology of CAD risk.
治疗性危险因素的改变提供了冠状动脉疾病(CAD)的显著降低

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Single-cell transcriptome dataset of human and mouse in vitro adipogenesis models.
人类和小鼠体外脂肪形成模型的单细胞转录组数据集。
  • DOI:
    10.1101/2023.03.27.534456
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Li,Jiehan;Jin,Christopher;Gustafsson,Stefan;Rao,Abhiram;Wabitsch,Martin;Park,ChongY;Quertermous,Thomas;Bielczyk-Maczynska,Ewa;Knowles,JoshuaW
  • 通讯作者:
    Knowles,JoshuaW
Environment-Sensing Aryl Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions.
  • DOI:
    10.1161/circulationaha.120.045981
  • 发表时间:
    2020-08-11
  • 期刊:
  • 影响因子:
    37.8
  • 作者:
    Kim JB;Zhao Q;Nguyen T;Pjanic M;Cheng P;Wirka R;Travisano S;Nagao M;Kundu R;Quertermous T
  • 通讯作者:
    Quertermous T
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THOMAS QUERTERMOUS其他文献

THOMAS QUERTERMOUS的其他文献

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{{ truncateString('THOMAS QUERTERMOUS', 18)}}的其他基金

Molecular mechanisms of vascular calcification and their connection to coronary disease risk
血管钙化的分子机制及其与冠心病风险的关系
  • 批准号:
    10673742
  • 财政年份:
    2022
  • 资助金额:
    $ 39.1万
  • 项目类别:
Elucidating Genotype-Phenotype Relationship of Polygenic Dilated Cardiomyopathies: Administrative Supplement (INCLUDE)
阐明多基因扩张型心肌病的基因型-表型关系:行政补充(包括)
  • 批准号:
    10404723
  • 财政年份:
    2021
  • 资助金额:
    $ 39.1万
  • 项目类别:
Identifying tobacco-genetic interactions through study of the aryl hydrocarbon receptor pathway.
通过研究芳基碳氢化合物受体途径来识别烟草与遗传的相互作用。
  • 批准号:
    10207112
  • 财政年份:
    2021
  • 资助金额:
    $ 39.1万
  • 项目类别:
Identifying tobacco-genetic interactions through study of the aryl hydrocarbon receptor pathway.
通过研究芳基碳氢化合物受体途径来识别烟草与遗传的相互作用。
  • 批准号:
    10372147
  • 财政年份:
    2021
  • 资助金额:
    $ 39.1万
  • 项目类别:
PDGFD regulates a transcriptional network to modulate smooth muscle cell transition and coronary artery disease risk
PDGFD 调节转录网络以调节平滑肌细胞转变和冠状动脉疾病风险
  • 批准号:
    10593934
  • 财政年份:
    2021
  • 资助金额:
    $ 39.1万
  • 项目类别:
Identifying tobacco-genetic interactions through study of the aryl hydrocarbon receptor pathway.
通过研究芳基碳氢化合物受体途径来识别烟草与遗传的相互作用。
  • 批准号:
    10591597
  • 财政年份:
    2021
  • 资助金额:
    $ 39.1万
  • 项目类别:
PDGFD regulates a transcriptional network to modulate smooth muscle cell transition and coronary artery disease risk
PDGFD 调节转录网络以调节平滑肌细胞转变和冠状动脉疾病风险
  • 批准号:
    10172666
  • 财政年份:
    2021
  • 资助金额:
    $ 39.1万
  • 项目类别:
PDGFD regulates a transcriptional network to modulate smooth muscle cell transition and coronary artery disease risk
PDGFD 调节转录网络以调节平滑肌细胞转变和冠状动脉疾病风险
  • 批准号:
    10385753
  • 财政年份:
    2021
  • 资助金额:
    $ 39.1万
  • 项目类别:
Single Cell Sequencing of Human iPSC-CM Subtype Identity and Function
人类 iPSC-CM 亚型身份和功能的单细胞测序
  • 批准号:
    9763916
  • 财政年份:
    2019
  • 资助金额:
    $ 39.1万
  • 项目类别:
Genetic and Stem Cell Model of Cardiac Metabolic Disease
心脏代谢疾病的遗传和干细胞模型
  • 批准号:
    9893900
  • 财政年份:
    2019
  • 资助金额:
    $ 39.1万
  • 项目类别:

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