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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：
10241961
负责人：
Paul Po Sheng cheng
金额：
$ 16.65万
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/10241961
关键词：
ATAC-seq Advisory Committees Affect Animal Model Arterial Fatty Streak Atherosclerosis Base Pairing Binding Biological Assay Biological Process Biology Cardiovascular Diseases Cause of Death Cell model Cell physiology Cells ChIP-seq Chromatin Remodeling Factor Chromosome 2 Clonality Clustered Regularly Interspaced Short Palindromic Repeats Code Computational Biology Coronary Arteriosclerosis Coronary artery Data Development Enhancers Epigenetic Process Epithelial 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 Lead 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 base career causal variant chromosome conformation capture design disorder risk epigenetic profiling epigenome editing epigenomics genetic risk factor genome editing genome wide association study genome-wide genomic locus in vivo in vivo Model insight multiple omics novel novel therapeutics prevent programs promoter research study response risk variant screening skills tool transcription factor transcriptome sequencing 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）仍然是美国和世界范围内的首要死亡原因。识别遗传风险因素和揭示潜在的生物过程将导致许多疾病的发展需要新的治疗途径。数十年的遗传学研究，特别是全基因组关联研究 (GWAS) 已发现许多与 CAD 风险增加相关的遗传位点。然而，这些基因座大部分位于非蛋白质编码区域。需要努力找出因果关系与这些基因座以及潜在的细胞过程和信号通路相关的基因。最近的表观基因组和转录组分析在前所未有的深度和分辨率方面取得了进展，靶向基因组/表观基因组编辑为识别特定基因和细胞提供了新的机会 CAD 中的机制。 K08 职业发展奖旨在启动首席研究员作为一名独立的医师科学家，利用互补的计算和分子方法发现人类心血管疾病遗传风险的机制并将其转化为研究结果纳入治疗。首席研究员的导师（Thomas Quertermous）是该领域的世界领先者动脉粥样硬化遗传风险的机制研究。拟议的培训还进一步补充了由计算生物学、遗传学和单细胞多组学分析领域的领导者组成的咨询委员会，包括 Michael Snyder、Erik Ingelsson、William Greenleef 和 Siddhartha Jaiswal 以及正式的教学课程斯坦福大学和冷泉港。在 F32 的资助下，主要研究者结合使用了体外和体内模型动脉粥样硬化并将 2q22 的非编码 CAD 风险位点与 ZEB2（一种具有在细胞状态转变中发挥关键作用。 ZEB2 似乎在表型调节中特异性上调动脉粥样硬化病变中的平滑肌细胞（SMC），并调节它们的细胞命运决定。拟议的研究将： (1) 确定 2q22 CAD 风险相关区域的因果调控要素； (2)揭示ZEB2影响SMC表型调节的分子机制； (3) 确定干扰平滑肌细胞 Zeb2 表达调节动脉粥样硬化的细胞机制体内病变。这项研究的结果将阐明调节动脉粥样硬化的新调节机制生物学。此外，首席研究员将获得过渡为独立研究员所需的培训专注于将人类心血管疾病的遗传发现转化为特定疾病的医师科学家机制和新疗法。