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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：
10469431
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/10469431
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.

摘要冠状动脉疾病（CAD）仍然是美国和世界范围内的主要死亡原因。识别遗传风险因素和揭示潜在的生物过程将导致许多发展需要新的治疗方法数十年的遗传学研究，特别是全基因组关联研究（GWAS），导致发现了许多与CAD风险增加相关的遗传基因座。然而，这些基因座中的大多数位于非蛋白质编码区。需要努力查明因果关系与这些基因座相关的基因以及潜在的细胞过程和信号通路。最近表观基因组学和转录组学分析在前所未有的深度和分辨率上取得了进展，沿着靶向基因组/表观基因组编辑提供了新的机会，以确定特定的基因和细胞 CAD中的机制 K 08职业发展奖旨在启动首席研究员的职业生涯，独立的医生科学家，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，并将其转化为发现治疗。主要研究者的导师（托马斯Quertermous）是动脉粥样硬化遗传风险的机制研究。拟议的培训还包括一个计算生物学、遗传学和单细胞多组学分析领导人咨询委员会，包括 Michael Snyder，Erik Ingelsson，William Greenleef，and Siddhartha Jaiswal，沿着正式的教学课程在斯坦福大学和冷泉港。在F32的资助下，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2 q22的非编码CAD风险基因座与ZEB 2（一种具有转录抑制因子的转录抑制因子）联系起来在细胞状态转换中的关键作用。ZEB 2似乎在表型调节的细胞中特异性上调，平滑肌细胞（SMC）在动脉粥样硬化病变，并调节其细胞命运的决定。拟议研究将：（1）确定2 q22时CAD风险相关区域的因果调节因素; (2)揭示ZEB 2影响SMC表型调节的分子机制;（3）确定ZEB 2对SMC表型调节的影响。平滑肌细胞Zeb 2表达紊乱调节动脉粥样硬化的细胞机制体内病变。本研究结果将阐明调节动脉粥样硬化的新的调节机制生物学此外，主要调查员将获得过渡到独立调查员所需的培训。医生科学家专注于将人类心血管疾病的遗传发现转化为特定的机制和新疗法。