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9 p21区域是遗传性心血管风险的最重要来源。该基因座独立于传统的风险因素，如吸烟，高血压和高脂血症，这表明它通过一种新的机制增强疾病。最具预测性的9 p21变异占个体终生冠状动脉疾病风险的20%以上。尽管与西方世界的主要死亡原因有关，但这些多态性导致血管疾病的机制仍不清楚。 在这项提案中，研究人员试图阐明9 p21风险位点的主要候选基因CDKN 2B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CDKN 2B可能通过对血管发芽和血管成熟的矛盾和拮抗作用来调节疾病的概念。该提案将汇集来自多个领域的公认专家，深度表型化的人类组织样本和独特的小鼠模型，旨在全面描述CDKN 2B的血管生物学。本申请包括三个具体目标，其将：1）绘制CDKN 2B调节血管稳定性的分子机制; 2）采用新的细胞特异性Cdkn 2b敲除动物来特异性地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;和3）确定在9 p21危险等位基因携带者中血管生成缺陷是否也促进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”9 p21基因座的生物学，并有助于在后GWAS时代的心血管遗传学领域。本提案过程中的发现旨在支持美国国立卫生研究院的既定使命，并提供有助于 从而为心血管疾病患者开发新的转化疗法。

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.