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：
10038543
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/10038543
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 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 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）仍然是美国和全球死亡的主要原因。识别遗传危险因素并揭示潜在的生物学过程将导致许多人的发展需要新的疗法途径。数十年的遗传学研究，尤其是基因组广泛的关联研究（GWAS）导致发现了许多遗传局部，与CAD风险增加相关。但是，这些基因座的大多数在于非蛋白质编码区域。需要努力来识别催化与这些局部和潜在的细胞过程和信号通路相关的基因。最近的前所未有的深度和分辨率的表观基因组和转录组学的进步以及靶向基因组/表观基因组编辑提供了识别特定基因和细胞的新机会 CAD中的机制。该K08职业发展奖旨在启动首席调查员的职业独立的物理科学家，利用完整的计算和分子方法发现为人类遗传风险构成心血管疾病的机制，并将其翻译发现治疗。首席调查员的导师（托马斯·奎勒姆）是世界领导者动脉粥样硬化遗传风险的机理研究。拟议的培训进一步补充了计算生物学，遗传学和单细胞多OMIC分析的领导咨询委员会，包括迈克尔·斯奈德（Michael Snyder），埃里克·英格斯森（Erik Ingelsson），威廉·格林勒夫（William Greenleef）和悉达多·贾斯瓦尔（Siddhartha 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风险基因座与Zeb2联系在一起，Zeb2是一种带有A的转录表示在细胞状态过渡中的关键作用。 Zeb2似乎在表型调制中被专门上调动脉粥样硬化病变中的平滑肌细胞（SMC），并调节其细胞命运决定。提议研究将：（1）确定负责CAD风险相关区域的因果监管元件，第2季度；（2）揭示了Zeb2影响SMC的表型调节的分子机制；（3）确定平滑肌细胞ZEB2表达的扰动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，原则研究者将获得过渡为独立的培训物理科学家专注于将人类心血管疾病的遗传发现转化为特定机制和新疗法。