From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease

从基因座到功能：ZEB2 在人类冠状动脉疾病风险中的作用

基本信息

批准号：
10900886
负责人：
Paul Po Sheng cheng
金额：
$ 10万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10900886
关键词：
ATAC-seq Advisory Committees Affect Animal Model Arterial Fatty Streak Atherosclerosis Base Pairing Binding Biological Assay Biological Process Biology CRISPR interference Cardiovascular Diseases Cause of Death Cell model Cell physiology Cells ChIP-seq Chromatin Remodeling Factor Chromosome 2 Clonal Expansion Clonality Clustered Regularly Interspaced Short Palindromic Repeats Code Computational Biology Coronary Arteriosclerosis Coronary artery Data Development Enhancers Epigenetic Process Epithelium Excision Funding Gene Expression Profiling Genes Genetic Genetic Epistasis Genetic Research Genetic Risk Genetic Transcription Genetic study Genome Genomic Segment Goals Heart Diseases Human Human Genetics In Vitro Individual K-Series Research Career Programs Lesion Link Luciferases MADH3 gene Malignant Neoplasms Mediating Mentors Mesenchymal Modeling Molecular Movement Mus Myocardial Infarction Persons Phenotype Physicians Play Principal Investigator Proteins Regulatory Element Research Personnel Resolution Risk Role Rupture Scientist Signal Pathway Single Nucleotide Polymorphism Smad Proteins Smooth Muscle Myocytes Stimulus Testing Training Transcription Repressor Transcriptional Regulation Translating Universities Untranslated RNA Work atherosclerosis risk career causal variant chromosome conformation capture design disorder risk epigenetic profiling epigenome editing epigenomic profiling genetic risk factor genome editing genome wide association study genome-wide genomic locus in vivo in vivo Model insight migration multiple omics novel novel therapeutics prevent programs promoter research study response risk variant screening skill acquisition tool transcription factor transcriptome sequencing transcriptomic profiling transcriptomics tumorigenesis

项目摘要

ABSTRACT Coronary artery disease (CAD) remains the leading cause of death in the U.S. and worldwide. Identifying genetic risk factors and uncovering the underlying biological processes will lead to the development of much needed new avenues for therapies. Decades of genetics research, especially genome wide association studies (GWAS), have led to the discovery of numerous genetic loci associated with an increased risk for CAD. However, the majority of these loci lie in non-protein-coding regions. Efforts are needed to identify causal genes associated with these loci and the underlying cellular processes and signaling pathways. Recent advances in epigenomic and transcriptomic profiling at unprecedented depth and resolution, along with targeted genome/epigenome editing provide new opportunities to identify specific genes and cellular mechanisms in CAD. This K08 career development award is designed to launch the principal investigator’s career as an independent physician scientist that utilizes complementary computational and molecular approaches to discover the mechanisms that underlies human genetic risk to cardiovascular disease and translates these findings into treatment. The principal investigator ‘s Mentor (Thomas Quertermous) is a world leader in mechanistic studies of genetic risk of atherosclerosis. The proposed training is further supplemented by an advisory committee of leaders in computational biology, genetics, and single-cell multi-omic analysis, including Michael Snyder, Erik Ingelsson, William Greenleef, and Siddhartha Jaiswal, along with formal didactic courses at Stanford University and Cold Spring Harbor. Funded by an F32, the principle investigator used a combination of in vitro and in vivo models of atherosclerosis and linked the non-coding CAD risk loci at 2q22 to ZEB2, a transcriptional repressor with a critical role in cell-state transitions. ZEB2 appears to be specifically up-regulated in phenotypically modulated smooth muscle cells (SMC) in atherosclerotic lesions, and modulates their cell-fate decisions. The proposed study will: (1) identify the causal regulatory element(s) responsible for the CAD-Risk-associated region at 2q22; (2) reveal the molecular mechanisms by which ZEB2 affects phenotypic modulation of SMC; (3) determine the cellular mechanism by which perturbation of smooth muscle cell Zeb2 expression modulates atherosclerotic lesions in vivo. The result of this study will elucidate new regulatory mechanisms that modulate atherosclerosis biology. Additionally, the principle investigator will gain the training needed to transition into an independent physician scientist focusing on translating genetic findings of human cardiovascular disease into specific mechanisms and novel therapies.

抽象的冠状动脉疾病（CAD）仍然是美国和全球识别的主要死亡原因遗传危险因素并揭示底层生物学过程将导致许多人的发展需要新的疗法途径。（GWAS），导致发现了许多遗传基因座与CAD风险增加有关。但是，这些基因座的大多数位于非蛋白质编码区域。基因与基因座和潜在的细胞过程和信号通路相关。前所未有的深度和分辨率的表观基因组和转录组分析的进步。靶向基因组/表观基因组编辑提供了新的机会来识别特定基因和细胞 CAD中的机制。该K08职业发展奖是为主要研究者的职业而设计的独立医师科学家，将互补的计算和分子分子倾斜到发现属于人类遗传风险的心血管疾病的机制并翻译到TheSESE 研究结果。动脉粥样硬化的遗传风险的机理研究。计算生物学，遗传学和单细胞多OMIC分析领导者的咨询委员迈克尔·斯奈德（Michael Snyder），埃里克·英格森（Erik Ingelson），威廉·格林勒夫（William Greenleef）和西德莎·贾斯瓦尔（Sidhartha Jaiswal）以及正式的教学课程在斯坦福大学和冷泉港。由F32资助，主要研究者使用了体外和体内模型的组合动脉粥样硬化，并将2q22的非编码CAD CAD风险基因座连接到Zeb2，Zeb2是一种带有A的转录阻遏物细胞状态转变中的关键作用。动脉粥样硬化病变中的平滑肌细胞（SMC），并调节其细胞效果研究将：（1）确定负责CAD风险相关区域的因果监管元件，第2季度；（2）启用Zeb2影响SMC的表型调制的分子机制；平滑肌细胞Zeb2表达模块化的细胞机制本研究的结果将阐明模块化的新规律机制生物学。专注于将人类心血管疾病的遗传发现重点转化为特定的医师科学家机制和新疗法。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular mechanisms of coronary artery disease risk at the PDGFD locus.

DOI：
10.1038/s41467-023-36518-9
发表时间：
2023-02-15
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Kim, Hyun-Jung;Cheng, Paul;Travisano, Stanislao;Weldy, Chad;Monteiro, Joao P.;Kundu, Ramendra;Nguyen, Trieu;Sharma, Disha;Shi, Huitong;Lin, Yi;Liu, Boxiang;Haldar, Saptarsi;Jackson, Simon;Quertermous, Thomas
通讯作者：
Quertermous, Thomas

von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis.

DOI：
10.1161/circulationaha.121.058427
发表时间：
2022-08-02
期刊：
CIRCULATION
影响因子：
37.8
作者：
Steffes, Lea C.;Cheng, Paul;Quertermous, Thomas;Kumar, Maya E.
通讯作者：
Kumar, Maya E.

Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque.

DOI：
10.1038/s44161-022-00042-8
发表时间：
2022-04
期刊：
NATURE CARDIOVASCULAR RESEARCH
影响因子：
0
作者：
Cheng, Paul;Wirka, Robert C;Kim, Juyong Brian;Kim, Hyun-Jung;Nguyen, Trieu;Kundu, Ramendra;Zhao, Quanyi;Sharma, Disha;Pedroza, Albert;Nagao, Manabu;Iyer, Dharini;Fischbein, Michael P;Quertermous, Thomas
通讯作者：
Quertermous, Thomas

Osimertinib-Associated Cardiomyopathy In Patients With Non-Small Cell Lung Cancer: A Case Series.

DOI：
10.1016/j.jaccao.2023.07.006
发表时间：
2023-12
期刊：
JACC: CARDIOONCOLOGY
影响因子：
11.1
作者：
Franquiz, Miguel J.;Waliany, Sarah;Xu, Audrey Yingwei;Hnatiuk, Anna;Wu, Sean M.;Cheng, Paul;Wakelee, Heather A.;Neal, Joel;Witteles, Ronald;Zhu, Han
通讯作者：
Zhu, Han

ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis.

DOI：
10.1161/circulationaha.121.057789
发表时间：
2022-02-08
期刊：
Circulation
影响因子：
37.8
作者：
Cheng P;Wirka RC;Shoa Clarke L;Zhao Q;Kundu R;Nguyen T;Nair S;Sharma D;Kim HJ;Shi H;Assimes T;Brian Kim J;Kundaje A;Quertermous T
通讯作者：
Quertermous T