From QTL to Gene for HDL Cholesterol

项目负责人/主要研究者（最后一位，第一位，中间一位）：P a i g n，B e v e r l y J 项目总结（见说明）： 心脏病是工业化社会的主要死因。生活方式的改变和许多药物 可用于降低低密度脂蛋白胆固醇做了很多，以减少心脏病，和主要途径 进一步的治疗进展在于学习如何提高高密度脂蛋白，一个主要的保护心脏病。 小鼠是寻找HDL基因的极好模型，因为小鼠中HDL的数量性状位点（QTL）是一个重要的基因。 小鼠和人在一致的位置被发现。 在延长期内，我们将测试Grin 3a、Etv 6、Chr 19上的5个基因的候选性，以及候选基因的候选性。 来自B6 xC 57 L杂交的基因。第一步是获得并测试每个人的淘汰模型。后 在这一代人中，这些模型将首先测试HDL胆固醇水平的差异。的差值 我们将从肝脏、脂肪组织和巨噬细胞中获得基因表达谱。这些 基因图谱将引导我们找到候选基因影响HDL代谢的途径。一旦 我们将假设基因在这些通路中的作用， 适当的实验来验证假设。 相关性（参见说明）： 主要目标是确定影响HDL胆固醇的基因和途径，从而提供保护 对抗主要的死亡原因心脏病识别这些HDL基因将发现新的药物 靶点，了解HDL调节的途径将阐明可能具有高密度脂蛋白的药物靶点。 对HDL的影响最大。提高高密度脂蛋白预计将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.