The role of CDKN2B in AAA disease

CDKN2B 在 AAA 疾病中的作用

• 批准号: 8466362
• 负责人: Nicholas James Leeper
• 金额: $ 13.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466362
• 关键词: 9p21; Abdominal Aortic Aneurysm; Accounting; Advisory Committees; Affect; Alleles; American; Aneurysm; Apoptosis; Apoptotic; Behavior; Berry Aneurysm; Biological Assay; Biology; Blood Vessels; CDKN2B gene; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cause of Death; Cell Cycle; Cell Death; Cell Proliferation; Cells; Chromosomes; Chromosomes, Human, Pair 9; Clinical; Coculture Techniques; Coronary; Coronary Arteriosclerosis; Culture Techniques; Cyclin-Dependent Kinase Inhibitor; Decision Making; Development; Digestion; Disease; Dyslipidemias; Eating; Elastases; Endothelium; Environmental Risk Factor; Enzymes; Equilibrium; Extracellular Matrix; Foundations; Functional RNA; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Heart; Heart Diseases; Human Genetics; Hyperlipidemia; Hypertension; In Vitro; Inflammation; Inflammatory; Infusion procedures; Inherited; Investigation; Investments; Knowledge; Lead; Ligands; Link; Malignant Neoplasms; Measurable; Measures; Medial; Mediating; Medicine; Mentors; Mission; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Patients; Peripheral Vascular Diseases; Phagocytosis; Play; Predisposition; Production; Progress Reports; Regulator Genes; Relative (related person); Research Personnel; Resistance; Resources; Risk; Risk Factors; Role; Rupture; Scientist; Signal Transduction; Single Nucleotide Polymorphism; Small Interfering RNA; Smoking; Smooth Muscle; Smooth Muscle Myocytes; Source; Techniques; Testing; Tissues; Training; Training Programs; United States; United States National Institutes of Health; Universities; Variant; Vascular Diseases; Western World; Work; cardiovascular disorder risk; cardiovascular risk factor; career; disorder risk; genome wide association study; human disease; in vivo; insight; lifetime risk; macrophage; migration; mortality; novel therapeutics; paracrine; programs; research study; skills

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.

描述(由申请者提供)：这项建议需要一个为期三年的培训计划，重点是为申请者在学术心血管医学领域的独立职业生涯做准备。该项目旨在传授申请者所需的技能和知识，以实现其长期目标，即对可遗传血管疾病的遗传基础做出贡献。申请者的直接培训目标是掌握关键的实验技术，完成将扩大他对先进分子生物学的理解的课程工作，发展自主运作所需的管理技能，并组成一系列工作，使其能够作为独立研究人员获得资金。在他的导师Tom Querterous和他精心挑选的斯坦福大学高级调查咨询委员会小组的指导下，申请者将拥有实现这些目标和过渡到独立的资源和支持。项目描述：全基因组关联(GWA)研究最近发现，染色体9p21的非编码区是心血管疾病遗传风险的最重要来源。与吸烟、高血压和高脂血症等传统风险因素无关，最具预测性的9p21变异占冠状动脉和外周血管疾病归因风险的21%。尽管被认为是西方世界的主要死因，但不幸的是，这些基因多态导致血管疾病的机制仍然是个谜。在这项提案中，研究人员试图阐明9p21基因间风险相关区域与腹主动脉瘤(AAA)疾病之间的关系。拟议的实验将建立在初步工作的基础上，该工作已暗示细胞周期调控基因CDKN2B是导致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，在风险等位基因携带者中高度下调。另一方面，它在血管系统中的活性仍不清楚。这项建议要研究的具体目标包括：(1)研究CDKN2B在体内对AAA形成和血管变性的影响(在小鼠弹性蛋白酶模型中)；以及(2)在体外确定CDKN2B在血管细胞凋亡和炎症中的作用。这些研究旨在为申请者在心血管遗传学和血管生物学的终身职业生涯奠定基础。在这项提议的过程中取得的发现旨在支持国家卫生研究院所宣布的使命，并为心血管疾病患者开发新的治疗方法作出贡献。