Cloning QTL Genes for Plasma HDL Cholesterol

克隆血浆 HDL 胆固醇 QTL 基因

• 批准号: 7089778
• 负责人: Beverly J Paigen
• 金额: $ 37.8万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-05 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089778
• 关键词: animal breeding; animal genetic material tag; atherosclerosis; biochemical evolution; bioinformatics; biotechnology; dietary lipid; disease /disorder model; functional /structural genomics; genetic mapping; genetic regulation; genetic susceptibility; genetically modified animals; high density lipoproteins; human genetic material tag; human tissue; laboratory mouse; linkage mapping; molecular cloning; quantitative trait loci

DESCRIPTION (provided by applicant): Atherosclerosis is the pathological basis for ischemic cardiovascular disease (CVD), the leading cause of death in the industrialized nations. Two lines of evidence indicate that high levels of plasma high-density lipoprotein cholesterol (HDL-C) protect against CVD. First, epidemiological studies have shown an inverse relationship between HDL-C levels and the incidence of CVD. Second, raising plasma HDL-C levels is associated with reduced atherosclerosis in mice, rabbits and humans. Because plasma HDL-C levels are largely genetically determined, quantitative trait locus (QTL) mapping has been used to localize HDL-regulating chromosomal (Chr) loci. Comparison of mouse and human HDL QTLs revealed that they are concordant, therefore finding genes underlying HDL-C QTLs in mice may reveal HDL-regulating genes in humans, which may provide therapeutic targets. Our long-term objective is to find new genes regulating plasma HDL-C levels to provide new therapeutic targets for CVD. In this proposal, we have chosen to identify the genes for one HDL-C QTL on Chr 1 (Hdlq33) and one on Chr 6 (Hdlq12) based on the following criteria: 1) at least one human homologous HDL-C QTL has been found; 2) the QTL has been found in multiple crosses, and/or they coincide with in silico HDL-C QTLs; 3) the QTL can be separated from closely linked QTL(s) so we know which crosses have detected the QTL we want to study; 4) the crosses involve sequenced strains (B6, A, DBA/2 and 129) because sequence differences will then be easier to find; and 5) other genetic resources are available: congenic strains, consomic strains, recombinant inbred strains. We propose to identify the genes of these two QTLs through the following specific aims. First, we will narrow the QTLs using genomic, statistical and bioinformatic tools. Second, we will narrow the QTLs genetically. Third, we will test candidate genes in mice according to their sequence, expression and functions, and test their relevance to human CVD in association studies. Through this grant, we will find genes that regulate blood HDL cholesterol (the so-called "good cholesterol") levels. Drugs acting on these genes may increase HDL cholesterol, and decrease the incidence of cardiovascular disease.

描述（由申请人提供）：动脉粥样硬化是缺血性心血管疾病（CVD）的病理基础，这是工业化国家死亡的主要原因。两条证据表明，高水平的血浆高密度脂蛋白胆固醇（HDL-C）预防CVD。首先，流行病学研究表明，HDL-C水平与CVD的发生率之间存在反比关系。其次，升高血浆HDL-C水平与小鼠，兔和人的动脉粥样硬化降低有关。由于血浆HDL-C水平在很大程度上是遗传确定的，因此已使用定量性状基因座（QTL）映射来定位HDL调节染色体（CHR）基因座。小鼠和人类HDL QTL的比较表明它们是一致的，因此在小鼠中找到基因的基因可能显示人类中的HDL调节基因，这可能提供治疗靶标。我们的长期目标是找到调节等离子体HDL-C水平的新基因，以为CVD提供新的治疗靶标。在此提案中，我们选择根据以下标准鉴定ChR 1（HDLQ33）上一个HDL-C QTL的基因，而在ChR 6（HDLQ12）上识别一个基因：1）至少有一个人类同源HDL-C QTL； 2）QTL已在多个十字架中发现，并且/或它们与硅HDL-C QTL相吻合； 3）QTL可以与紧密链接的QTL分开，因此我们知道哪些十字检测到了我们要研究的QTL； 4）十字涉及测序应变（B6，A，DBA/2和129），因为序列差异将变得更容易找到； 5）还有其他遗传资源：先天性菌株，综合菌株，重组近交菌株。我们建议通过以下特定目的识别这两个QTL的基因。首先，我们将使用基因组，统计和生物信息学工具来缩小QTL。其次，我们将从遗传上缩小QTL。第三，我们将根据小鼠的序列，表达和功能来测试候选基因，并测试它们与人类CVD的关联研究中的相关性。通过这笔赠款，我们将找到调节血液HDL胆固醇（所谓的“胆固醇”）水平的基因。作用于这些基因的药物可能会增加HDL胆固醇，并降低心血管疾病的发生率。