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）：心脏病仍然是工业化社会的主要死亡原因，即使生活方式的改变和降低LDL胆固醇的有效药物已经降低了其发病率。进一步治疗进展的主要途径在于学习如何提高HDL，这是预防心脏病的主要保护措施;据估计，HDL的适度增加可能导致心脏病发病率的大幅下降。小鼠是寻找HDL基因及其编码蛋白质的极好模型。不仅在小鼠和人类中发现HDL的数量性状基因座（QTL）在一致的位置，而且小鼠模型可用于确定提高HDL水平的多态性是否也降低动脉粥样硬化风险。我们相信，通过识别一个复杂性状背后的所有（或几乎所有）基因，我们会学到很多东西。我们认为，HDL是最好的复杂性状，这样一个事业，因为大量的基础设施的HDL QTL的研究在小鼠，连锁和全基因组关联的研究在人类中，以及相当多的知识HDL代谢。对这一复杂特征的任何深入了解，都将对我们思考其他导致许多重大疾病的复杂特征的方式产生相当大的影响。在此资助期间，目标1将确定7个额外的QTL基因，影响HDL使用遗传和生物信息学工具的组合，已证明在过去几年中如此成功。当我们确定这些基因时，有些可能在HDL代谢中具有已知的功能;然而，其他基因可能是相当新的，它们调节HDL水平的机制可能完全未知。对于这些新的基因，重要的是，我们验证他们在HDL代谢中的作用与额外的证据。因此，在目标2中，我们建议通过进行转基因或敲除/敲入，通过其他功能研究以及通过在人群中测试这些基因（通过合作）来获得额外的证据。最后，在目标3中，我们建议研究QTL基因的相互作用以及它们如何相互作用形成网络。 公共卫生相关性：心脏病是工业化社会的主要死亡原因，尽管生活方式的改变和降低LDL胆固醇的有效药物已经降低了其发病率。进一步治疗进展的主要途径在于学习如何提高HDL，这提供了对心脏病的保护。这项建议旨在确定HDL数量性状基因座的因果基因，其中一些可能是很好的药物靶点。