The paradoxical role of CDKN2B in blood vessel sprouting and maturation

描述(由申请人提供)：全基因组关联研究(GWAS)最近发现染色体9p21的一个区域是可遗传心血管风险的最重要来源。该基因座与吸烟、高血压和高脂血症等传统危险因素无关，表明它通过一种新的机制加重疾病。最具预测性的9p21变异占个人一生患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死因，但这些基因多态性导致血管疾病的机制(S)仍不清楚。在这项提案中，研究人员试图阐明9p21风险基因座的一个主要候选基因CDKN2B与血管疾病之间的关系。具体地说，他们将质疑该基因在血管生成中的作用，以及CDKN2B可能通过对血管萌发和血管成熟的矛盾和拮抗作用来调节疾病的概念。这项建议将汇集来自多个领域的公认专家、深入表型的人类组织样本和独特的小鼠模型，目的是全面描述CDKN2B的血管生物学。这项应用包括三个具体目标：1)绘制CDKN2B调节血管稳定的分子机制图；2)利用新型细胞特异性CDKN2B基因敲除动物来具体确定哪种细胞类型调节对缺血的病理反应，以及该过程是否可逆；以及3)确定血管生成缺陷是否也会促进携带9p21风险等位基因的人类的动脉粥样硬化斑块脆弱性和心肌梗死。这些研究的目的是“反向翻译”9p21基因座的生物学，并为后GWAS时代的心血管遗传学领域做出贡献。在这项提案的过程中所做的发现旨在支持国家卫生研究院所宣称的使命，并提供将 导致为心血管疾病患者开发新的转化性疗法。

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.