From QTL to Gene for HDL Cholesterol

项目主任/首席调查员(最后、第一、中间)：P a I g e n，B e v e r L y J 项目摘要(请参阅说明)： 心脏病是工业化社会的主要死亡原因。生活方式的改变和许多药物 可降低低密度脂蛋白胆固醇对减少心脏病有很大作用，而主要途径 进一步的治疗进展取决于学习如何提高高密度脂蛋白，高密度脂蛋白是预防心脏病的主要保护措施。 小鼠是寻找高密度脂蛋白基因的极佳模型，因为高密度脂蛋白的数量性状基因座(QTL) 老鼠和人被发现在一致的位置。 在延长期内，我们将对GRIN3A、ETV6、CHR 19上的5个基因和候选基因进行候选测试 来自B6xC57L杂交的基因。第一步是获得并测试它们各自的淘汰型模型。之后 在这一代，这些模型将首先测试高密度脂蛋白胆固醇水平的差异。当不同之处 ，我们将获得肝脏、脂肪组织和巨噬细胞的基因表达谱。这些 图谱将引导我们找到候选基因影响高密度脂蛋白新陈代谢的途径。一次 这些途径被识别，我们将假设基因在途径和设计中的作用 适当的实验来检验这一假说。 相关性(请参阅说明)： 主要目标是确定影响高密度脂蛋白胆固醇的基因和途径，高密度脂蛋白胆固醇提供保护 对抗主要的死亡原因，心脏病。识别这些高密度脂蛋白基因将发现新药 靶点，并了解高密度脂蛋白调节的途径将阐明药物靶点可能具有 对高密度脂蛋白的影响最大。据预测，提高高密度脂蛋白可以降低心脏病的发病率。

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.