EPISTATIC REGULATORY MECHANISMS OF CORONARY HEART DISEASE RISK

冠心病风险的上位调节机制

• 批准号: 9769843
• 负责人: Clint L Miller
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769843
• 关键词: 3' Untranslated Regions; Accidents; Advisory Committees; Alleles; Area; Arterial Fatty Streak; Automobile Driving; Binding; Binding Sites; Bioinformatics; Biometry; Blood Vessels; Cardiac development; Cardiovascular Diseases; Cardiovascular system; Chromatin; Collaborations; Complement Factor D; Complex; Coronary Arteriosclerosis; Coronary artery; Coronary heart disease; Critical Pathways; Data; Development; Development Plans; Disease; Embryo; Epistatic Gene; Ethnic group; Feedback; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Epistasis; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic Variation; Genome; Genomic Segment; Genomics; Goals; Guide RNA; Heart Injuries; Heritability; Human; Human Genetics; In Vitro; Knowledge; LIF gene; Laboratories; Lasers; Lead; Ligands; Light; Link; Lung diseases; Malignant Neoplasms; Maps; Mediating; Mentorship; Mission; Molecular; Molecular Genetics; Mus; Pathway interactions; Phase; Phenotype; Physiology; Platelet-Derived Growth Factor; Population; Positioning Attribute; Post-Transcriptional Regulation; Predisposition; Proteins; Public Health; Reagent; Regulation; Regulator Genes; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Science; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Statistical Data Interpretation; Technology; Testing; Therapeutic; Tissues; Training; Training Programs; Transcription Factor AP-1; Transcriptional Regulation; United States National Institutes of Health; Universities; Untranslated RNA; Untranslated Regions; Variant; Work; activator 1 protein; atherogenesis; atherosclerosis risk; base; cardiovascular pharmacology; career; career development; causal variant; combinatorial; disorder risk; experience; gene environment interaction; genetic architecture; genetic variant; genome wide association study; heart disease risk; human disease; in vivo; innovation; insight; multimodality; next generation; next generation sequencing; novel therapeutics; racial and ethnic; response; response to injury; risk variant; skill acquisition; skills; therapeutic development; trait; transcription factor

DESCRIPTION (provided by applicant): PROJECT SUMMARY The purpose of this five-year proposal is to provide an integrative and personalized training program for the applicant to transition into an independent academic position in the cardiovascular sciences. The long-term goal is to discover new treatments for cardiovascular disease through investigating the signaling mechanisms upstream of genome-wide associations. The applicant already has a strong background in cardiovascular pharmacology, physiology, and signal transduction by employing both in vitro and in vivo experimental approaches. This career development plan (K99 phase) will provide additional training in human genetics and genomic analyses employing innovative next-generation sequencing technologies, as well as sophisticated gene-targeting approaches to investigate the regulatory function of causal variants associated with coronary heart disease. The applicant will also receive a wealth of informal and didactic training at Stanford University i specialized areas such as genomic and statistical analyses, and professional development skills, which will be critical for the applicant to gain autonomy and launch a productive career as an independent investigator. Under the expert mentorship of Dr. Thomas Quertermous, MD and the assembled advisory committee (Dr. Assimes, Dr. Tsao, Dr. Pritchard, and Dr. Greenleaf) the applicant will receive the necessary guidance and resources to accomplish these goals and efficiently transition to independence during the R00 phase. The research topic of this proposal fulfills a significant knowledge gap in the field by identifying the missing mechanistic links between common genetic variants and heritable coronary heart disease. As much as half the risk of developing atherosclerotic coronary heart disease (CHD) is genetically predetermined. Genome-wide association studies have now identified multiple independent genetic regions which together account for a fraction (~10%) of the estimated heritability for coronary heart disease (~60%). Gene-gene (epistatic) and gene-environment interactions between common susceptibility regions are predicted to explain this "hidden" heritability. However, the causal mechanisms by which genetic variation alters disease risk remain largely unknown. Deciphering these regulatory networks is predicted to reveal new insights into disease risk and therapeutic development strategies. Next-generation sequencing approaches have now accelerated our understanding of how non-coding variation alters disease-related gene expression. The goal of this project is to investigate the molecular and genetic interactions responsible for driving risk t two genes, the vascular development transcription factor, TCF21, and the platelet-derived growth factor D (PDGFD). Both of these genes have been associated with heart disease risk in multiple racial/ethnic groups, act independently of traditional risk factors, and are key regulator of smooth muscle cell responses during cardiac development and injury. We previously identified a regulatory mechanism for the TCF21 association involving both transcriptional and post-transcriptional regulation of TCF21 gene expression in coronary artery smooth muscle cells. Recently, we systematically mapped TCF21 transcription factor protein to directly bind and trans-activate the PDGFD locus, and observed a positive correlation of TCF21 and PDGFD expression in human atherosclerotic lesions. Consistently, PDGF-mediated signaling was enriched at TCF21 binding sites and CHD risk loci overall. Based on these findings, we hypothesize that regulation of TCF21 may be pivotal to the SMC phenotypic response to injury in the vessel wall, and that molecular and genetic interactions between the TCF21 and PDGFD loci potentiates expression of these genes, leading to increased coronary atherosclerosis risk. This hypothesis will be empirically tested by pursuing the following specific aims: 1) Dissect the causal mechanisms of regulatory variants at TCF21 and PDGFD loci. 2) Investigate the molecular interactions between the TCF21 and PDGFD loci. To achieve these aims, we will integrate high-throughput genomics in primary diseased human coronary artery tissue with RNA-guided genome targeting in human coronary artery SMC and in mouse embryos in vivo. Ultimately, this work will shed new light on targeting critical pathways associated with "hidden" CHD risk in various human populations, and enable the development of the next generation of therapeutics.

描述（由申请人提供）：项目摘要该五年提案的目的是为申请人提供一个综合性和个性化的培训计划，以过渡到心血管科学中的独立学术职位。长期目标是通过研究全基因组关联上游的信号传导机制来发现心血管疾病的新疗法。申请人通过使用体外和体内实验方法，在心血管药理学，生理学和信号转导方面具有强大的背景。该职业发展计划（K99阶段）将提供有关使用创新的下一代测序技术的人类遗传学和基因组分析的额外培训，以及研究与冠心心脏病相关的因果变异的调节功能的复杂基因靶向方法。申请人还将在斯坦福大学I专业领域（例如基因组和统计分析）以及专业发展技能等大量非正式和教学培训，这对于申请人获得自治和启动富有成效的职业至关重要。 独立研究者。在医学博士托马斯·Quermentous博士和集会咨询委员会（Assimes博士，Tsao博士，Pritchard博士和Greenleaf博士）的专家指导下，申请人将获得必要的指导和资源，以实现这些目标并有效地过渡到R00阶段。该提案的研究主题通过确定常见的遗传变异与可遗传的冠心病之间缺失的机械联系来弥补现场的显着知识差距。在遗传上预先确定的动脉粥样硬化冠心病（CHD）的风险高达一半。全基因组关联研究现已确定了多个独立的遗传区域，这些区域占冠心病估计遗传力的一部分（约10％）（约60％）。预计共同敏感性区域之间的基因基因（上毒）和基因环境相互作用可以解释这种“隐藏”的遗传力。但是，遗传变异改变疾病风险的因果机制仍然在很大程度上未知。预计这些监管网络的解密将揭示有关疾病风险和治疗发展策略的新见解。现在，下一代测序方法已经加速了我们对非编码变异如何改变与疾病相关的基因表达的理解。该项目的目的是研究导致风险t两个基因的分子和遗传相互作用，即血管发育转录因子TCF21和血小板衍生的生长因子D（PDGFD）。这两个基因均与多个种族/族裔的心脏病风险有关，独立于传统危险因素，并且是心脏发育和损伤期间平滑肌细胞反应的关键调节剂。我们先前鉴定了TCF21关联的调节机制，该机制涉及冠状动脉平滑肌细胞中TCF21基因表达的转录和转录后调节。最近，我们系统地映射了TCF21转录因子蛋白，以直接结合和反式激活PDGFD基因座，并观察到人动脉粥样硬化病变中TCF21和PDGFD表达的正相关。一致地，PDGF介导的信号传导在TCF21结合位点富集，而CHD风险基因座总体上富含。根据这些发现，我们假设TCF21的调节可能与SMC表型对血管壁的损伤反应至关重要，并且TCF21和PDGFD基因座之间的分子和遗传相互作用增强了这些基因的表达，从而导致冠状动脉粥样硬化的风险增加。该假设将通过追求以下特定目的进行经验检验：1）剖析TCF21和PDGFD基因座的调节变体的因果机制。 2）研究TCF21和PDGFD基因座之间的分子相互作用。为了实现这些目的，我们将在人类冠状动脉SMC和体内小鼠胚胎中与RNA引导的基因组靶向RNA引导的基因组靶向，将高通量基因组与RNA引导的基因组靶向进行整合。最终，这项工作将为针对与各种人群中“隐藏” CHD风险相关的关键途径的关键途径提供新的启示，并能够发展下一代治疗剂。

项目成果

TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells.

• DOI: 10.1371/journal.pgen.1006750
• 发表时间: 2017-05
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Kim JB;Pjanic M;Nguyen T;Miller CL;Iyer D;Liu B;Wang T;Sazonova O;Carcamo-Orive I;Matic LP;Maegdefessel L;Hedin U;Quertermous T
• 通讯作者: Quertermous T

An automatic entropy method to efficiently mask histology whole-slide images.

• DOI: 10.1038/s41598-023-29638-1
• 发表时间: 2023-03-15
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Song, Yipei;Cisternino, Francesco;Mekke, Joost M. M.;de Borst, Gert J. J.;de Kleijn, Dominique P. V.;Pasterkamp, Gerard;Vink, Aryan;Glastonbury, Craig A. A.;van der Laan, Sander W. W.;Miller, Clint L. L.
• 通讯作者: Miller, Clint L. L.

Intersecting single-cell transcriptomics and genome-wide association studies identifies crucial cell populations and candidate genes for atherosclerosis.

• DOI: 10.1093/ehjopen/oeab043
• 发表时间: 2022-01
• 期刊: European heart journal open
• 作者: Slenders L;Landsmeer LPL;Cui K;Depuydt MAC;Verwer M;Mekke J;Timmerman N;van den Dungen NAM;Kuiper J;de Winther MPJ;Prange KHM;Ma WF;Miller CL;Aherrahrou R;Civelek M;de Borst GJ;de Kleijn DPV;Asselbergs FW;den Ruijter HM;Boltjes A;Pasterkamp G;van der Laan SW;Mokry M
• 通讯作者: Mokry M

GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease.

• DOI: 10.3389/fcvm.2018.00072
• 发表时间: 2018
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Turner AW;Wong D;Dreisbach CN;Miller CL
• 通讯作者: Miller CL