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:
  • 金额:
    $ 58.63万
  • 依托单位:
  • 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

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.
项目摘要 复杂的血管疾病,如冠状动脉疾病(CAD)、心肌梗死(MI)和冠状动脉粥样硬化性心脏病(CHD)。 动脉钙化(CAC)在世界范围内造成相当大公共卫生负担, 环境风险因素的影响。鉴于人类血管疾病的患病率不断上升, 因此,迫切需要新的治疗和预防措施,针对主要的 血管壁中的疾病过程。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基因位点。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致病基因、变体和途径,并证明了共享的遗传学特征。 病因学然而,将这些基因发现转化为生物学和生物学方法仍然是一个挑战。 临床相关的见解。超过一半的CAD/MI位点与经典风险无关 这些因素可能导致血管功能障碍。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,但在动脉粥样硬化中起关键作用,因为它们的收缩性 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。 利用多组学和数量性状基因定位在人冠状动脉SMC和组织,我们最近 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 研究表明CAD相关转录因子(如TCF 21)在冠心病的发病中起着关键作用。 调节动脉粥样硬化过程中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),我们还确定了新的SMC特异性转录调控因子,与多种 血管疾病综合精细映射分析优先考虑四个半LIM域5(FHL 5)作为 CAD/MI和亚临床血管疾病的致病基因。有趣的是,FHL 5过表达减少, SMC收缩性,增殖和钙化增加,与CAC的遗传相关性一致。 最后,SMC中的FHL 5染色质和转录组分析支持其作为转录辅因子的作用, 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 反式调节途径可以解决这些病症的多效性风险机制。在此,我们计划 在离体人血管细胞和动脉中进行FHL 5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在血管功能障碍中的作用, 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,并构建多基因组学研究平台。 基因调控网络,以确定FHL 5调节组对亚临床和晚期疾病的影响 结果。这些研究将揭示多种血管疾病的关键调控级联反应和生物标志物, 这些疾病的早期治疗或预防策略,以消除这些使人衰弱的疾病。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Clint L Miller其他文献

Clint L Miller的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Clint L Miller', 18)}}的其他基金

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
  • 批准号:
    10636849
  • 财政年份:
    2022
  • 资助金额:
    $ 58.63万
  • 项目类别:
Cis-regulatory architecture of coronary vascular wall loci
冠状血管壁位点的顺式调控结构
  • 批准号:
    10609005
  • 财政年份:
    2019
  • 资助金额:
    $ 58.63万
  • 项目类别:
Cis-regulatory architecture of coronary vascular wall loci
冠状血管壁位点的顺式调控结构
  • 批准号:
    10395440
  • 财政年份:
    2019
  • 资助金额:
    $ 58.63万
  • 项目类别:
EPISTATIC REGULATORY MECHANISMS OF CORONARY HEART DISEASE RISK
冠心病风险的上位调节机制
  • 批准号:
    9769843
  • 财政年份:
    2014
  • 资助金额:
    $ 58.63万
  • 项目类别:

相似海外基金

How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
  • 批准号:
    2315783
  • 财政年份:
    2023
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
  • 批准号:
    2719534
  • 财政年份:
    2022
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
  • 批准号:
    20K01113
  • 财政年份:
    2020
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633211
  • 财政年份:
    2020
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2436895
  • 财政年份:
    2020
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633207
  • 财政年份:
    2020
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
  • 批准号:
    19K01745
  • 财政年份:
    2019
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
  • 批准号:
    426559561
  • 财政年份:
    2019
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
  • 批准号:
    2236701
  • 财政年份:
    2019
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Studentship
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
  • 批准号:
    415543446
  • 财政年份:
    2019
  • 资助金额:
    $ 58.63万
  • 项目类别:
    Research Fellowships
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了