The role of CDKN2B in AAA disease

描述（由申请人提供）：该提案需要一个为期三年的培训计划，重点是准备申请人在学术心血管医学的独立职业生涯。该项目旨在传授申请人所需的技能和知识，以实现他的长期目标，即对遗传性血管疾病的遗传基础做出贡献。申请人的直接培训目标是掌握关键的实验技术，执行课程，这将扩大他对先进分子生物学的理解，发展自主运作所需的管理技能，并组成一个工作机构，这将使资金作为一个独立的调查员。在他的导师Tom Quertermous和他精心挑选的斯坦福大学高级调查员咨询委员会小组的指导下，申请人将获得实现这些目标并向独立过渡的资源和支持。项目描述：全基因组关联（GWA）研究最近确定了染色体9 p21的非编码区作为心血管疾病遗传风险的最重要来源。独立于吸烟、高血压和高脂血症等传统危险因素，最具预测性的9 p21变异占冠状动脉和外周血管疾病归因风险的21%。尽管与西方世界的主要死亡原因有关，但不幸的是，这些多态性导致血管疾病的机制仍然是一个谜。在这项提案中，研究人员试图阐明9 p21基因间风险相关区域与腹主动脉瘤（AAA）疾病之间的关系。建议的实验将建立在初步工作的基础上，该工作涉及细胞周期调控基因CDKN 2B，作为临床疾病的致病基因。该基因控制细胞命运决策的几个方面，并在风险等位基因携带者中高度下调。另一方面，其在脉管系统中的活性仍然未知。本提案中研究的具体目的将包括：（1）表征CDKN 2B对AAA形成和血管变性的体内作用（在小鼠弹性蛋白酶模型中）;和（2）体外确定CDKN 2B在平滑肌细胞凋亡和炎症中的作用。这些研究旨在为申请人的心血管遗传学和血管生物学终身职业奠定基础。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，并为开发心血管疾病患者的新疗法做出贡献。 公共卫生相关性：相关性：科学家们还不了解遗传变异如何导致心血管疾病。最近的研究已经确定9号染色体和细胞调节基因CDKN 2B可能是遗传疾病风险的来源。了解这些通路的功能可能会导致心脏和血管疾病的新疗法-目前在美国的主要杀手。

DESCRIPTION (provided by applicant): This proposal entails a three-year training program focused on preparing the applicant for an independent career in academic cardiovascular medicine. This project aims to impart the skills and knowledge required for the applicant to achieve his long-term goal of contributing insights into the genetic underpinnings of heritable vascular disease. The immediate training objectives of the applicant are to master critical experimental techniques, perform coursework that will expand his understanding of advanced molecular biology, develop administrative skills required to function autonomously, and compose a body of work that will enable funding as an independent investigator. Under the guidance of his mentor, Tom Quertermous, and his carefully selected panel of Advisory Committee of senior investigators at Stanford University, the applicant will have the resources and support to achieve these goals and transition to independence. Project Description: Genome-wide association (GWA) studies have recently identified a non-coding region of chromosome 9p21 as the most important source of heritable risk for cardiovascular disease. Independent of traditional risk factors such as smoking, hypertension and hyperlipidemia, the most predictive 9p21 variants account for as much as 21% of the attributable risk for coronary and peripheral vascular disease. Despite being implicated in the leading cause of death in the Western world, the mechanism by which these polymorphisms lead to vascular disease unfortunately remains a mystery. In this proposal, the investigators seek to elucidate the relationship between the intergenic risk-associated region of 9p21 and abdominal aortic aneurysm (AAA) disease. Proposed experiments will build on preliminary work which has implicated the cell- cycle regulatory gene, CDKN2B, as the causative gene responsible for clinical disease. This gene controls several aspects of cell-fate decision making and is highly downregulated in carriers of the risk-allele. On the other hand, its activity in the vasculature remains unknown. Specific aims to be investigated in this proposal will include: (1) Characterizing the in vivo effects of CDKN2B on AAA formation and blood vessel degeneration (in the mouse elastase model); and (2) Determining the role of CDKN2B in smooth muscle cell apoptosis and inflammation, in vitro. These studies are intended to form the foundation of a lifelong career in cardiovascular genetics and vascular biology for the applicant. 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 therapies for patients with cardiovascular disease. PUBLIC HEALTH RELEVANCE: Relevance: Scientists do not yet understand how genetic variation causes cardiovascular disease. Recent studies have identified chromosome 9 and the cell-regulating gene, CDKN2B, as possible sources of inherited risk for disease. Understanding how these pathways function might lead to new therapies for heart and blood vessel disorders- currently the leading killers in the United States.