The paradoxical role of CDKN2B in blood vessel sprouting and maturation

CDKN2B 在血管萌芽和成熟中的矛盾作用

基本信息

批准号：
9173040
负责人：
Nicholas James Leeper
金额：
$ 46.66万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-15 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9173040
关键词：
9p21 Animals Apoptosis Arterial Fatty Streak Atherosclerosis Biological Assay Biology Blood Vessels CDKN2B gene Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Cause of Death Cell physiology Cells Chromosomes Chromosomes, Human, Pair 9 Coculture Techniques Cohort Studies Collaborations Coronary Arteriosclerosis Defect Development Disease Dominant-Negative Mutation Endothelial Cells Enrollment Event Genes Genetic Genetic Polymorphism Genetic Risk Genetic Variation Genetic study Heart Hemorrhage Heritability Hindlimb Human Hyperlipidemia Hypertension Hypoxia Impairment In Vitro Individual Inherited Intramuscular Ischemia Lead Ligation Limb structure Link Maps Mediating Mission Molecular Molecular Genetics Mus Myocardial Infarction Operative Surgical Procedures Pathologic Pathway interactions Patients Pericytes Peripheral arterial disease Phagocytosis Phenotype Phosphorylation Process Publishing Quantitative Trait Loci Recruitment Activity Research Personnel Risk Risk Factors Role Rupture Sampling Scientist Secondary to Signal Transduction Smoking Smooth Muscle Myocytes Source TP53 gene Tissue Sample Transfection Transgenic Organisms Translating Tube Tumor Suppressor Proteins United States United States National Institutes of Health Variant Vascular Diseases Vascular Endothelial Growth Factors Western World Work angiogenesis atherogenesis base cardiovascular risk factor cell behavior cell type disorder risk femoral artery genome wide association study human tissue in vivo insight knockout animal lifetime risk macrophage man matrigel mouse model neovascularization novel novel therapeutics pleiotropism public health relevance response risk variant

项目摘要

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have recently identified a region of chromosome 9p21 as the most important source of heritable cardiovascular risk. This locus is independent of traditional risk factors such as smoking, hypertension and hyperlipidemia, suggesting it potentiates disease via a novel mechanism. The most predictive 9p21 variants account for more than 20% of an individual's lifetime risk for coronary artery disease. Despite being implicated in the leading cause of death in the Western world, the mechanism(s) by which these polymorphisms lead to vascular disease remain unclear. In this proposal, the investigators seek to elucidate the relationship between a leading candidate gene at the 9p21 risk locus, CDKN2B, and vascular disease. Specifically, they will query the role of this gene in angiogenesis, and the concept that CDKN2B may regulate disease via a paradoxical and antagonistic effect on blood vessel sprouting, and blood vessel maturation. This proposal will bring together recognized experts from several fields, deeply phenotyped human tissue samples and unique mouse models with the objective of fully describing the vascular biology of CDKN2B. This application includes three specific aims which will: 1) Map the molecular mechanism by which CDKN2B regulates blood vessel stabilization; 2) Employ novel cell-specific Cdkn2b knockout animals to specifically determine which cell type regulates the pathologic response to ischemia, and whether the process is reversible; and 3) Determine whether the angiogenic defect also promotes atherosclerotic plaque vulnerability and myocardial infarction in human carriers of the 9p21 risk allele. The objective of these studies is to 'reverse translate' the biology of the 9p21 locus and contribute to the field of cardiovascular genetics in the post-GWAS era. Discoveries made in the course of this proposal are intended to support the stated mission of the National Institutes of Health and provide contributions that will lead to the development of new translational therapies for patients with cardiovascular disease.

描述（由申请人提供）：全基因组关联研究 (GWAS) 最近确定染色体 9p21 的一个区域是遗传性心血管风险的最重要来源。该基因座独立于吸烟、高血压和高脂血症等传统危险因素，表明它通过一种新机制加剧疾病。最具预测性的 9p21 变异占个体终生冠状动脉疾病风险的 20% 以上。尽管被认为是西方世界的主要原因，但这些多态性导致血管疾病的机制仍不清楚。在该提案中，研究人员试图阐明 9p21 风险位点的主要候选基因 CDKN2B 与血管疾病之间的关系。具体来说，他们将质疑该基因在血管生成中的作用，以及 CDKN2B 可能通过对血管萌芽和血管成熟的矛盾和拮抗作用来调节疾病的概念。该提案将汇集多个领域的知名专家、深度表型的人体组织样本和独特的小鼠模型，旨在全面描述 CDKN2B 的血管生物学。该应用包括三个具体目标：1) 绘制 CDKN2B 调节血管稳定性的分子机制； 2）采用新型细胞特异性Cdkn2b敲除动物来特异性确定哪种细胞类型调节缺血的病理反应，以及该过程是否可逆； 3) 确定血管生成缺陷是否也会促进 9p21 风险等位基因携带者的动脉粥样硬化斑块易损性和心肌梗死。这些研究的目的是“反向翻译”9p21位点的生物学，并为后GWAS时代的心血管遗传学领域做出贡献。本提案过程中取得的发现旨在支持美国国立卫生研究院的既定使命，并提供以下贡献：导致心血管疾病患者新转化疗法的开发。