High-Resolution Systems Genetic Studies of Atherosclerotic Lesion Composition

动脉粥样硬化病变成分的高分辨率系统遗传学研究

基本信息

批准号：
8436419
负责人：
Brian Joseph Bennett
金额：
$ 24.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2012-04-16 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8436419
关键词：
Accounting Address Apolipoprotein E Arterial Fatty Streak Atherosclerosis Biochemical Biological Markers Biology Blood Blood Pressure Breeding California Candidate Disease Gene Cardiovascular Diseases Cause of Death Cells Cessation of life Choline Chromosomes, Human, Pair 2 Clinic Clinical Complex Coronary Arteriosclerosis Data Data Analyses Development Development Plans Diet Dominant-Negative Mutation Enzymes FMO3 Fatty acid glycerol esters Gene Expression Genes Genetic Genetic Determinism Genetic Risk Genetic Variation Genotype Goals Hepatic Human Hybrids Inflammatory Laboratories Lead Lesion Lipids Liver Los Angeles Maps Mentors Methods Modeling Molecular Analysis Mouse Strains Mus Myocardial Infarction Oxides Pathway interactions Persons Phenotype Positioning Attribute Postdoctoral Fellow Predisposition Principal Investigator Public Health RNA Research Research Personnel Resolution Risk Risk Factors Scientist Series Stroke Structure of brachiocephalic artery Susceptibility Gene System Testing Training Training Programs Transcript Transgenic Mice United States Universities Validation Variant abstracting apolipoprotein B-100 base career development design economic impact flavin-containing monooxygenase genetic analysis genetic variant hypercholesterolemia improved in vivo innovation macrophage metabolomics new therapeutic target novel post-doctoral training programs research study response skills small hairpin RNA small molecule trait

项目摘要

Abstract: This proposal describes a 5-year training program to facilitate the transition to an independent academic position. The principal investigator has completed 4 years of post-doctoral training at the University of California, Los Angeles, and now, will expand upon his scientific skills by developing an integrative career development program consisting of both a rigorous research plan and detailed career development plan. This program will further develop several unique integrative genetics approaches to cardiovascular disease. Aldons J. Lusis will continue to mentor the principal investigator's scientific development. Dr. Lusis is a recognized leader in mouse genetics and has made several significant contributions to the understanding of atherosclerosis and lipid biology. More importantly, Dr. Lusis has successfully trained a number of investigators who have become independent academic scientist. Cardiovascular disease, CVD, remains the leading cause of death in the United States accounting for almost 1 million deaths in 2002 and an estimated economic impact in excess of 393 billion dollars in 2005. There remains limited understanding of the genes predisposing a person to death from CVD. The primary aim of this proposal is designed to use a high-resolution mapping approach recently developed in out laboratory to identify genes associated with both atherosclerotic lesion size and cellular composition. Several of these novel variants will be investigated after the trainee transitions to an independent position. In addition to gene identification, several experiments are described that characterize and test a genetic network associated with lesion size in a model of advanced atherosclerosis in the mouse. The third aim tests a novel candidate for a novel metabolite associated with atherosclerosis. The methods and analyses used in Aims 2 and 3 are the basis for gene selection and validation of novel targets identified in Aim 1 as the candidate transitions to an independent position. A long-term goal of studies proposed in this application is the identification of novel therapeutic targets for cardiovascular disease by using a systems genetics approach where mouse genetics is integrated with gene expression, small molecule metabolite profiling and extensive atherosclerotic lesion phenotyping.

抽象的：该提案描述了一个为期 5 年的培训计划，以促进向独立的过渡学术地位。主要研究者已在该所完成了4年的博士后培训现在，加州大学洛杉矶分校将通过开发一种综合职业发展计划，包括严格的研究计划和详细的职业生涯发展计划。该计划将进一步开发几种独特的心血管综合遗传学方法疾病。 Aldons J. Lusis 将继续指导首席研究员的科学发展。博士。 Lusis 是小鼠遗传学领域公认的领导者，并为该领域做出了多项重大贡献。了解动脉粥样硬化和脂质生物学。更重要的是，Lusis博士成功培养了一名成为独立学术科学家的研究人员数量。心血管疾病仍然是美国人口死亡的主要原因 2002 年有近 100 万人死亡，估计经济影响超过 3930 亿美元 2005 年。对于导致人死于 CVD 的基因的了解仍然有限。这该提案的主要目的是使用最近开发的高分辨率绘图方法实验室鉴定与动脉粥样硬化病变大小和细胞组成相关的基因。在实习生过渡到独立职位后，将研究其中一些新颖的变体。除了基因鉴定之外，还描述了一些表征和测试基因的实验。小鼠晚期动脉粥样硬化模型中与病变大小相关的遗传网络。第三个目标测试了与动脉粥样硬化相关的新型代谢物的新候选物。方法和目标 2 和目标 3 中使用的分析是基因选择和验证新目标的基础目标 1：候选人过渡到独立职位。本申请中提出的研究的长期目标是确定新的治疗方法通过使用系统遗传学方法来确定心血管疾病的目标，其中小鼠遗传学是与基因表达、小分子代谢物分析和广泛的动脉粥样硬化病变相结合表型分析。