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
- 来源:
- 关键词:
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.
治疗危险因素的修饰已在冠状动脉疾病(CAD)中显着降低
然而,西方人群的重大风险是由于影响疾病的常见遗传变异
容器壁上的途径,并且在没有特定疗法的情况下保持较低的理解。促进我们的长期
表征这种遗传风险的分子基础的目标,我们参与了全基因组
协会研究(GWAS)确定与冠状动脉疾病(CAD)风险相关的等位基因变异,这些差异
努力产生了数百个相关的基因座。但是,大多数确定的因果变异属于
在蛋白质编码外显子之外,在理解不佳的基因组的调节区域中,进一步
需要努力了解关联机制,从而了解疾病的风险。我们的中心假设
是疾病等位基因变异的重要子集主要调节长的非编码RNA(LNCRNA)
表达,具有调节因果蛋白编码基因(PCGENE)表达的作用
基因组相互作用,例如染色体环。我们的目的是调查这些lncrnas的作用
发挥介导CAD因果PCGENES的表达,以及实现这一目标的机制
功能。我们的理由是,lncRNA是遗传和表观遗传学之间的关键中介
信号传导以及阐明其功能机制是理解CAD风险的关键方面。获得
有关这些分子在CAD背景下的基本信息,我们建议
研究人类冠状动脉平滑肌细胞(HCASMC)LNCRNA。在AIM 1中,我们将确定lncrnas
通过与疾病相关的刺激在这些细胞中调节,并将其映射到CAD GWAS基因座。共表达网络
分析将将这些LNCRNA连接到PCGENES,并启动网络和途径分析以开始
建立他们的生物功能关联。在AIM 2中,我们将绘制表达式定量特质基因座变体
(eqtls)对于每个LNCRNA,使用高通量等位基因特异性表达方法
低丰度RNA的定量。将研究发现的lncRNA eqtls,以确定是否是否
它们与CAD GWAS因果变异以及基因组分子性状QTL共定位。 CRISPR基因组
编辑将用于验证EQTL,并确认PCGENE身份。在AIM 3中,我们将雇用CRISPR
抑制和单细胞RNA测序(perturbseq)以绘制由由
与疾病相关的LNCRNA,还研究了它们的体外细胞对HCASMC的影响。这些研究将是
在我们对主要培养的HCASMC的大量作品的帮助,表征了表观基因组修饰,染色质
可访问性和循环以及我们绘制CAD GWAS因果变体和基因的努力,这些变体和基因介导了风险
该单元格类型。这项工作具有很高的创新性,因为它结合了一个高度开发的独特基因组数据集
疾病相关的细胞类型,并且很重要,因为它将整合LNCRNA,其调节性变异和
分子机制进入CAD风险的病因。
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
共 2 条
- 1
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Identifying tobacco-genetic interactions through study of the aryl hydrocarbon receptor pathway.
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- 财政年份:2021
- 资助金额:$ 39.1万$ 39.1万
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PDGFD regulates a transcriptional network to modulate smooth muscle cell transition and coronary artery disease risk
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- 财政年份:2021
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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:1059159710591597
- 财政年份:2021
- 资助金额:$ 39.1万$ 39.1万
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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:1017266610172666
- 财政年份:2021
- 资助金额:$ 39.1万$ 39.1万
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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:1038575310385753
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人类 iPSC-CM 亚型身份和功能的单细胞测序
- 批准号:97639169763916
- 财政年份:2019
- 资助金额:$ 39.1万$ 39.1万
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