Genetic Analysis of Proteoglycan-Mediated Lipoprotein Clearance

蛋白多糖介导的脂蛋白清除的遗传分析

基本信息

批准号：
8230531
负责人：
Jeffrey D Esko
金额：
$ 44.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-07-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230531
关键词：
Abbreviations Adenoviruses Albumins Apolipoproteins Atherosclerosis Binding Biochemical Biological Assay Blood Blood Circulation Candidate Disease Gene Cells Chylomicrons Complex Coronary Arteriosclerosis Deacetylase Defect Diabetes Mellitus Disaccharides Dyslipidemias Elements Engineering Enzymes Etiology Family GAG Gene Genes Genetic Glucosamine Glycosaminoglycans Grant Heparan Sulfate Biosynthesis Heparan Sulfate Proteoglycan Heparinoids Heparitin Sulfate Hepatic Hepatocyte High Density Lipoproteins Human Hypertriglyceridemia IDL lipoproteins Iduronic Acid In Vitro Isotope Labeling LDL-Receptor Related Protein 1 LDL-Receptor Related Proteins Length Lipolysis Lipoprotein Binding Lipoprotein Receptor Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Measures Mediating Membrane Modeling Mus Mutant Strains Mice Mutation Patients Peptide Hydrolases Peripheral Perisinusoidal Space Pharmaceutical Preparations Polysaccharides Process Protein Family Proteoglycan Rattus Relative (related person)Risk Role SR-BI receptor Series Site Structure System Transgenes Translating Transmembrane Domain Triglycerides Very low density lipoprotein Work Xylose chronic alcohol ingestion genetic analysis hepatic lipase in vivo interest lipid biosynthesis lipolysis-stimulated receptor lipoprotein lipase lipoprotein triglyceride liquid chromatography mass spectrometry member mutant promoter public health relevance receptor receptor mediated endocytosis recombinase sulfation sulfotransferase syndecan uptake

项目摘要

DESCRIPTION (provided by applicant): Genetic Analysis of Proteoglycan-Mediated Lipoprotein Clearance. Hypertriglyceridemia results from the accumulation of triglyceride-rich lipoproteins (TRLs) in the circulation (chylomicrons, very low-density lipoproteins, and their remnants). Because patients with hypertriglyceridemia have increased risk for atherosclerosis and coronary artery disease, considerable interest exists in understanding its etiology and therapy. TRL accumulation can arise from altered lipid biosynthesis, apolipoproteinemias, and alterations in lipolysis in the peripheral circulation. It can also arise from defective clearance of lipoprotein remnants in the liver, which occurs through a multi-step process involving sequestration of remnant lipoproteins in the space of Disse and receptor-mediated endocytosis by hepatocytes. Hepatocytes express several receptors, including members of the LDL receptor family and Syndecan-1 (Sdc1), a trans-membrane heparan sulfate proteoglycan. Studies of Sdc1-deficient mice showed that Sdc1 is the primary proteoglycan receptor that mediates TRL clearance. Additionally, hepatocyte-specific inactivation of the heparan sulfate biosynthetic enzymes, GlcNAc N-deacetylase/N-sulfotransferase-1 (Ndst1) and uronyl 2-O-sulftotransferase (Hs2st) using the Cre-loxP system demonstrated the importance of the heparan sulfate chains of Sdc1. Mutant mice bearing defects in heparan sulfate biosynthesis and Sdc1 provide a model for defining genes relevant to hypertriglyceridemia in humans. To better understand how Sdc1 and heparan sulfate structure relate to lipoprotein clearance in the liver, we have the following specific aims: Aim 1. Determine the structural features of Syndecan-1 that facilitate its action as a lipoprotein receptor in vivo. Aim 2. Explore the structural features of heparan sulfate required for lipoprotein clearance in vivo. Aim 3. Characterize the impact of mutations on Syndecan-1 structure and lipoprotein binding in vitro. Aim 4. Investigate the relative contribution of Syndecan-1 to hepatic clearance of triglyceride-rich lipoproteins in human and mouse hepatocytes. Our genetic analysis of HSPGs in the mouse support the idea that changes in liver heparan sulfate could be an underlying cause of human dyslipidemias. Thus, determining the relevant genes involved in HSPG synthesis in the liver and their functional role in remnant clearance provides a series of candidate genes for eventual allelic analysis in patients with hypertriglyceridemia. PUBLIC HEALTH RELEVANCE:. Hypertriglyceridemia results from the accumulation of triglyceride in the circulation and can occur as a result of genetic deficiencies or as a consequence of chronic alcohol consumption, uncontrolled diabetes, and various drug treatments. Because patients with hypertriglyceridemia have increased risk for atherosclerosis and coronary artery disease, considerable interest exists in understanding its cause and therapy. This grant focuses on understanding how receptors in the liver clear triglycerides from the blood and concentrates in particular of the role of heparan sulfate in this process.

描述（由申请人提供）：蛋白聚糖介导的脂蛋白清除的遗传分析。高甘油三酯血症是由于循环中富含甘油三酯的脂蛋白（TRL）（乳糜微粒、极低密度脂蛋白及其残余物）的积累引起的。由于高甘油三酯血症患者患动脉粥样硬化和冠状动脉疾病的风险增加，因此人们对了解其病因和治疗有很大兴趣。 TRL 积累可能是由于脂质生物合成的改变、载脂蛋白血症和外周循环中脂肪分解的改变引起的。它也可能是由于肝脏中脂蛋白残余物的清除缺陷引起的，这是通过一个多步骤过程发生的，涉及残余脂蛋白在 Disse 空间中的隔离和肝细胞受体介导的内吞作用。肝细胞表达多种受体，包括 LDL 受体家族成员和 Syndecan-1 (Sdc1)（一种跨膜硫酸乙酰肝素蛋白聚糖）。对 Sdc1 缺陷小鼠的研究表明，Sdc1 是介导 TRL 清除的主要蛋白聚糖受体。此外，使用 Cre-loxP 系统对硫酸乙酰肝素生物合成酶、GlcNAc N-脱乙酰酶/N-磺基转移酶-1 (Ndst1) 和糖醛酰 2-O-磺基转移酶 (Hs2st) 进行肝细胞特异性灭活，证明了硫酸乙酰肝素链的重要性Sdc1 的。硫酸乙酰肝素生物合成和 Sdc1 缺陷的突变小鼠提供了一个模型，用于定义与人类高甘油三酯血症相关的基因。为了更好地了解 Sdc1 和硫酸乙酰肝素结构与肝脏中脂蛋白清除率的关系，我们有以下具体目标：目标 1. 确定 Syndecan-1 的结构特征，以促进其作为体内脂蛋白受体的作用。目标2.探索体内脂蛋白清除所需的硫酸乙酰肝素的结构特征。目标 3. 表征突变对 Syndecan-1 结构和体外脂蛋白结合的影响。目标 4. 研究 Syndecan-1 对人和小鼠肝细胞中富含甘油三酯的脂蛋白的肝脏清除的相对贡献。我们对小鼠 HSPG 的遗传分析支持这样的观点：肝脏硫酸乙酰肝素的变化可能是人类血脂异常的根本原因。因此，确定肝脏中 HSPG 合成所涉及的相关基因及其在残余物清除中的功能作用，为高甘油三酯血症患者的最终等位基因分析提供了一系列候选基因。公共卫生相关性：。高甘油三酯血症是由甘油三酯在循环中积聚引起的，可能是由于遗传缺陷或长期饮酒、不受控制的糖尿病和各种药物治疗造成的。由于高甘油三酯血症患者患动脉粥样硬化和冠状动脉疾病的风险增加，因此人们对其病因和治疗非常感兴趣。该资助的重点是了解肝脏中的受体如何清除血液中的甘油三酯，并特别关注硫酸乙酰肝素在此过程中的作用。