The role of CDKN2B in AAA disease

CDKN2B 在 AAA 疾病中的作用

基本信息

批准号：
8661240
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
项目类别：
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/8661240
关键词：
9p21 Abdominal Aortic Aneurysm Accounting Advisory Committees Affect 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 risk variant skills

项目摘要

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（由申请人提供）：该提案需要为期三年的培训计划，重点是为申请人在学术心血管医学领域的独立职业做好准备。该项目旨在传授申请人所需的技能和知识，以实现其长期目标，即深入了解遗传性血管疾病的遗传基础。申请人的直接培训目标是掌握关键的实验技术，完成课程以扩大他对先进分子生物学的理解，培养自主运作所需的管理技能，并撰写一系列工作，以便作为独立研究者获得资助。在导师 Tom Quertermous 及其精心挑选的斯坦福大学高级研究人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 的非编码区域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危险因素无关，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高达 21%。尽管被认为是西方世界的主要原因，但不幸的是，这些多态性导致血管疾病的机制仍然是个谜。在该提案中，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，该工作表明细胞周期调节基因 CDKN2B 是临床疾病的致病基因。该基因控制细胞命运决策的多个方面，并且在风险等位基因携带者中高度下调。另一方面，它在脉管系统中的活性仍然未知。该提案要研究的具体目标包括： (1) 表征 CDKN2B 对 AAA 形成和血管变性的体内影响（在小鼠弹性蛋白酶模型中）； (2)体外确定CDKN2B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在心血管遗传学和血管生物学领域的终身职业生涯奠定基础。该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，并为心血管疾病患者新疗法的开发做出贡献。