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，在工业化国家是导致死亡的主要原因。两种证据表明高水平的血浆高密度脂蛋白胆固醇（HDL-C）可以预防心血管疾病。首先，流行病学研究表明HDL-C水平与心血管疾病发病率呈反比关系。第二，提高血浆HDL-C水平与小鼠、兔子和人类的动脉粥样硬化减少有关。由于血浆HDL-C水平在很大程度上是由遗传决定的，数量性状位点（QTL）定位已被用于定位hdl调节染色体（Chr）位点。小鼠和人类HDL QTLs的比较显示它们是一致的，因此在小鼠中发现HDL- c QTLs的相关基因可能会发现人类中HDL调节基因，从而可能提供治疗靶点。我们的长期目标是找到调节血浆HDL-C水平的新基因，为心血管疾病提供新的治疗靶点。在本提案中，我们选择了基于以下标准鉴定一个位于Chr 1 （Hdlq33）和一个位于Chr 6 （Hdlq12）的HDL-C QTL的基因：1)至少发现了一个人类同源HDL-C QTL；2)该QTL存在于多个杂交中，且/或与硅质HDL-C QTL重合；3) QTL可以从紧密连锁的QTL中分离出来，这样我们就知道哪些杂交检测到了我们想要研究的QTL；4)杂交涉及已测序的菌株（B6、A、DBA/2和129），因为这样更容易发现序列差异；5)其他遗传资源：同源菌株、同源菌株、重组近交系。我们建议通过以下具体目的来鉴定这两个qtl的基因。首先，我们将使用基因组学、统计学和生物信息学工具来缩小qtl的范围。其次，我们将从基因上缩小qtl。第三，我们将根据候选基因的序列、表达和功能在小鼠中进行测试，并在关联研究中测试它们与人类心血管疾病的相关性。通过这笔拨款，我们将找到调节血液中高密度脂蛋白胆固醇（所谓的“好胆固醇”）水平的基因。作用于这些基因的药物可能会增加高密度脂蛋白胆固醇，并降低心血管疾病的发病率。