From QTL to Gene for HDL Cholesterol

从 QTL 到 HDL 胆固醇基因

• 批准号: 8836570
• 负责人: Beverly J Paigen
• 金额: $ 42.66万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836570
• 关键词: Adipose tissue; Affect; Bioinformatics; Candidate Disease Gene; Cause of Death; Chromosome Mapping; Drug Targeting; Gene Expression; Generations; Genes; Genetic; Genetic Engineering; Goals; Grant; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Incidence; Instruction; Knock-out; LDL Cholesterol Lipoproteins; Learning; Life Style; Liver; Location; Maps; Metabolism; Modeling; Molecular Profiling; Mouse Strains; Mus; Pathway interactions; Pharmaceutical Preparations; Principal Investigator; Quantitative Trait Loci; Regulation; Resources; Role; Societies; Testing; Therapeutic; Time; design; improved; macrophage; novel; programs; research study; tool

Program Director/Principal Investigator {Last, First, Middle): P a i g e n , B e v e r l y J PROJECT SUMMARY (See instnjctions}: Heart disease is the major cause of death in industrialized societies. Lifestyle changes and the many drugs available to reduce LDL cholesterol have done a great deal to reduce heart disease, and the major avenue to further therapeutic progress lies in learning how to raise HDL, a major protection against heart disease. The mouse is an excellent model for finding HDL genes because the quantitative trait loci (QTL) for HDL in mouse and human are found in concordant locations. In the extension period we will test the candidacy of Grin3a, Etv6, the 5 genes on Chr 19, and the candidate genes from the B6xC57L cross. The first step is to obtain and test knockout models for each of them. After the generation, these models will first be tested for differences in HDL cholesterol levels. When a difference is observed, we will obtain gene expression profiles from liver, adipose tissue, and macrophages. These profiles will direct us toward the pathway through which the candidate gene impacts HDL metabolism. Once these pathways are identified we will hypothesize the role of the gene within the pathway and design appropriate experiments to test the hypothesis. RELEVANCE (See instructions): The major goal is to identify the genes and pathways that affect HDL cholesterol, which provides protection against the leading cause of death, heart disease. Identifying these HDL genes will uncover novel drug targets, and understanding the pathways of HDL regulation will elucidate the drug targets likely to have the greatest impact on HDL. Raising HDL is predicted to decrease heart disease incidence.

项目总监/首席研究员（最后、第一、中间）：P a igen , Beverly J 项目摘要（参见说明}： 心脏病是工业化社会中死亡的主要原因。生活方式的改变和许多药物 降低低密度脂蛋白胆固醇对减少心脏病有很大作用，主要途径 进一步的治疗进展在于学习如何提高高密度脂蛋白（HDL），这是预防心脏病的主要手段。 小鼠是寻找 HDL 基因的绝佳模型，因为 HDL 的数量性状位点 (QTL) 小鼠和人类被发现处于一致的位置。 在延长期内，我们将测试Grin3a、Etv6、Chr 19上的5个基因的候选基因以及候选基因 来自 B6xC57L 杂交的基因。第一步是获取并测试它们的淘汰模型。后 在这一代中，这些模型将首先测试 HDL 胆固醇水平的差异。当有差异时 观察后，我们将获得肝脏、脂肪组织和巨噬细胞的基因表达谱。这些 配置文件将引导我们了解候选基因影响高密度脂蛋白代谢的途径。一次 确定这些途径后，我们将假设基因在途径和设计中的作用 适当的实验来检验假设。 相关性（参见说明）： 主要目标是确定影响高密度脂蛋白胆固醇的基因和途径，从而提供保护 对抗导致死亡的主要原因——心脏病。识别这些 HDL 基因将发现新药 靶点，了解 HDL 调节途径将阐明可能具有以下作用的药物靶点： 对 HDL 的影响最大。预计提高 HDL 可以降低心脏病的发病率。