Cloning QTL Genes for Plasma HDL Cholesterol

克隆血浆 HDL 胆固醇 QTL 基因

• 批准号: 7895203
• 负责人: Beverly J Paigen
• 金额: $ 44.93万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895203
• 关键词: Adopted; Affect; Atherosclerosis; Bioinformatics; Biological; Cause of Death; Cholelithiasis; Chromosomes; Cloning; Collaborations; Complex; Disease; Drug Delivery Systems; Engineering; Foundations; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Goals; Grant; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hypertension; Incidence; Intervention; Knock-out; Knowledge; LDL Cholesterol Lipoproteins; Lead; Learning; Life Style; Link; Literature; Location; Meta-Analysis; Metabolic syndrome; Metabolism; Methodology; Mind; Modeling; Mus; Obesity; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Population; Public Health; QTL Genes; Quantitative Trait Loci; Regulation; Research Infrastructure; Rest; Risk; Role; Route; Societies; Testing; Therapeutic; Transgenic Organisms; Work; diabetes risk; gene function; genome wide association study; insight; mouse model; novel; public health relevance; reverse cholesterol transport; tool; trait

DESCRIPTION (provided by applicant): Heart disease is still the major cause of death in industrialized societies even though lifestyle changes and effective drugs that lower LDL cholesterol have reduced its incidence. The major avenue to further therapeutic progress lies in learning how to raise HDL, a major protection against heart disease; it has been estimated that a modest increase in HDL could lead to a large decrease in heart disease incidence. The mouse is an excellent model for finding HDL genes and the proteins they encode. Not only are quantitative trait loci (QTLs) for HDL in mouse and human found in concordant locations, but the mouse model can be used to determine whether a polymorphism that raises HDL levels also reduces atherosclerosis risk. We believe that we would learn much by identifying all (or nearly all) of the genes underlying one complex trait. We suggest that HDL is the best complex trait for such an undertaking because of the substantial infrastructure of HDL QTL studies in the mouse, linkage and genome wide association studies in humans, and considerable knowledge about HDL metabolism. Any insights into this complex trait will have considerable relevance to the ways in which we think about other complex traits responsible for many of our major diseases. In this grant period, Aim 1 will be to identify 7 additional QTL genes that affect HDL using the combination of genetic and bioinformatic tools that have proven so successful during the last few years. When we identify these genes, some may have a known function in HDL metabolism; others, however, may be quite new, and the mechanisms by which they modulate HDL levels may be completely unknown. For these novel genes, it is important that we verify their role in HDL metabolism with additional evidence. Therefore in Aim 2 we propose to obtain that extra evidence by making transgenics or knockouts/knockins, by other functional studies, and by testing these genes in human populations (by collaboration). Finally in Aim 3, we propose to study the interactions of QTL genes and how they work with each other to form networks. PUBLIC HEALTH RELEVANCE: Heart disease is the major cause of death in industrialized societies even though lifestyle changes and effective drugs that lower LDL cholesterol have reduced its incidence. The major avenue to further therapeutic progress lies in learning how to raise HDL, which provides protection against heart disease. This proposal seeks to identify the genes causal for HDL quantitative trait loci; some of them may be good drug targets.

描述（由申请人提供）：即使生活方式的改变和有效的药物降低了LDL胆固醇的发病率，心脏病仍然是工业社会中死亡的主要原因。进一步治疗进展的主要途径在于学习如何提高HDL，这是对心脏病的主要保护；据估计，HDL的适度增加可能导致心脏病的发病率大大降低。小鼠是查找HDL基因及其编码蛋白质的绝佳模型。在一致位置发现的小鼠和人类中HDL的定量性状基因座（QTL）不仅是用于确定升高HDL水平的多态性是否还会降低动脉粥样硬化风险的多态性。我们认为，通过识别一个复杂特征的基因的所有（或几乎所有）基因，我们将学到很多东西。我们建议HDL是这种事业的最佳复杂性状，因为在人类中，HDL QTL研究的大量基础架构是对HDL QTL研究的实质性基础设施，并且对HDL代谢有了相当多的知识。对这一复杂特征的任何见解都将与我们思考其他负责我们许多主要疾病的其他复杂特征的方式具有相当大的相关性。在这一赠款期间，目标1将是使用遗传和生物信息学工具的组合确定影响HDL的7个其他QTL基因，这些工具在过去几年中已被证明是如此成功。当我们识别这些基因时，有些可能在HDL代谢中具有已知功能。但是，其他可能是非常新的，并且它们调节HDL水平的机制可能完全未知。对于这些新颖的基因，重要的是要验证它们在HDL代谢中的作用，并有其他证据。因此，在AIM 2中，我们建议通过其他功能研究制作转基因或敲除/敲除蛋白，并通过在人类种群中测试这些基因（通过协作）来获得额外的证据。最后，在AIM 3中，我们建议研究QTL基因的相互作用以及它们如何相互工作以形成网络。 公共卫生相关性：心脏病是工业社会中的主要死亡原因，即使生活方式的改变和有效的药物降低了LDL胆固醇的发病率。进一步治疗进展的主要途径在于学习如何提高HDL，从而提供对心脏病的保护。该建议旨在识别HDL定量性状基因座的基因因果。其中一些可能是好的药物靶标。