The role of CDKN2B in efferocytosis and atherosclerosis

CDKN2B 在胞吞作用和动脉粥样硬化中的作用

基本信息

批准号：
9247021
负责人：
Nicholas James Leeper
金额：
$ 40.36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247021
关键词：
9p21 Affinity Agonist Apolipoprotein E Apoptosis Apoptotic Arterial Fatty Streak Atherosclerosis Behavior Biological Assay Biology Blood Vessels Bone Marrow Transplantation CD47 gene Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Cause of Death Cell surface Cells Chromosomes Chromosomes, Human, Pair 9 Coculture Techniques Collaborations Confocal Microscopy Coronary Arteriosclerosis Data Development Disease model Eating Employee Strikes Excision Gene Expression Profiling Genes Genetic Genetic Polymorphism Genetic Variation Genetic study Growth Heart Heart Diseases Heritability Human Genetics Hyperlipidemia Hypertension Impairment In Vitro Individual Inflammatory Inherited Knock-out Lead Lesion Ligands Link Luciferases Mediating Methods Mission Modeling Mus Necrosis Oral PPAR gamma Pathologic Pathway interactions Patients Phagocytes Phagocytosis Pharmacogenomics Phenocopy Phenotype Phosphatidylserines Predisposition Process Reagent Reporter Research Personnel Risk Risk Factors Role Safety Scientist Secondary to Series Signal Transduction Smoking Source Specific qualifier value Specificity Testing Tissues Toxicology Tracer Transactivation Translating Tumor Suppressor Proteins United States United States National Institutes of Health Variant Vascular Diseases Western World atherogenesis base calreticulin cardiovascular disorder risk disorder risk genome wide association study humanized antibody in vivo lifetime risk lipid metabolism loss of function macrophage mimetics mouse model novel novel therapeutics prevent public health relevance receptor risk variant transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have recently identified a region of chromosome 9p21 as the most important source of heritable risk for cardiovascular disease. This locus is independent of traditional risk factors such as smoking, hypertension and hyperlipidemia, and 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 atherosclerosis. Specifically, they will query the role of this gene in a process known as "efferocytosis", which is the phagocytic clearance of apoptotic debris. They will investigate how this process regulates the growth of the necrotic core in the developing atherosclerotic plaque and determine the downstream consequences of impaired efferocytosis. This proposal will bring together recognized experts from several fields, highly specialized translational reagents and unique mouse models with the objective of fully describing the vascular biology of CDKN2B. This application includes two specific aims which will: 1) Employ novel lineage tracing and cell-specific knockout models to determine how failed efferocytosis signaling regulates pro-atherosclerotic phenotype switching in the developing plaque; and 2) Test the translational utility of a novel high-affinity humanized antibody which may stimulate the removal of necrotic debris and induce atherosclerotic plaque regression. 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.

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 的一个区域是心血管疾病遗传风险的最重要来源，该位点与吸烟、高血压和高脂血症等传统风险因素无关。，最具预测性的 9p21 变异占个体一生中冠状动脉疾病风险的 20% 以上，尽管它是西方世界的主要死亡原因。这些多态性导致血管疾病的机制仍不清楚。在本提案中，研究人员试图阐明 9p21 风险位点的主要候选基因 CDKN2B 与动脉粥样硬化之间的关系。他们将研究这个过程如何调节坏死核心的生长。该提案将汇集多个领域的知名专家、专门的转化试剂和独特的小鼠模型，旨在全面描述 CDKN2B 的血管生物学。目标将：1）采用新的谱系追踪和细胞特异性敲除模型来确定失败的胞吞作用信号如何调节正在形成的斑块中的促动脉粥样硬化表型转换； 2）测试翻译效用一种新型高亲和力人源化抗体的研究，该抗体可以刺激坏死碎片的清除并诱导动脉粥样硬化斑块消退，这些研究的目的是“反向翻译”9p21位点的生物学特性，并为后期心血管遗传学领域做出贡献。 -GWAS 时代。在本提案过程中取得的发现旨在支持国立卫生研究院的既定使命，并为实现这一目标做出贡献。为心血管疾病患者开发新的转化疗法。