Screens for novel compounds to correct diabetic postprandial dyslipidemia

筛选纠正糖尿病餐后血脂异常的新型化合物

基本信息

批准号：
7651625
负责人：
Kevin Jon Williams
金额：
$ 37.5万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7651625
关键词：
Action Potentials Anabolism Apolipoproteins B Area Atherosclerosis Automation Binding Biological Biological Assay Biological Factors Carbohydrates Cardiovascular Diseases Catabolism Cause of Death Cell surface Cells Cholesterol Chylomicrons Cleaved cell Clinical Trials Collaborations Collection Confusion Cytochalasin D Data Deacetylase Defect Development Diabetes Mellitus Dyslipidemias Employee Strikes Enzymes Ethnopharmacology Evaluation FDA approved Fluorescence Funding Genistein Goals Head Heparan Sulfate Proteoglycan Heparin Heparitin Sulfate Hepatic Hepatocyte Human Hypertriglyceridemia Inorganic Sulfates Insulin-Dependent Diabetes Mellitus Intestines Knock-out Knowledge Label Laboratories Length Letters Libraries Life Ligand Binding Domain Lipoproteins Liver Liver Circulation Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Mediator of activation protein Metabolic Methods Miniaturization Modeling Molecular Molecular Mechanisms of Action Molecular Target Morphologic artifacts Mus NIH Program Announcements Non-Insulin-Dependent Diabetes Mellitus Outcome Participant Pathway interactions Patients Peripheral Pharmaceutical Preparations Phenotype Physiological Physiology Plasma Polymers Preclinical Drug Evaluation Preparation Primary carcinoma of the liver cells Proteins Public Health Publications Publishing Radioactive Reading Reagent Reproducibility Resources Role Route Screening procedure Seminal Side Specific qualifier value Structure Surface Syndrome Testing Therapeutic Tissues Titrations Triglycerides Unspecified or Sulfate Ion Sulfates Validation Work apolipoprotein B receptor apolipoprotein B-48 assay development base cardiovascular risk factor diabetic diabetic patient expectation heparanase heparitinase high throughput screening in vivo insight knock-down lipoprotein cholesterol neglect non-diabetic novel novel strategies particle polypeptide public health relevance receptor response restoration small molecule sugar sulfation sulfotransferase type I and type II diabetes uptake

项目摘要

DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease remains the major cause of death in patients with type 1 and type 2 diabetes mellitus (T1DM, T2DM). Atherosclerosis arises from the retention of cholesterol-rich, apolipoprotein-B (apoB)-lipoproteins within the vessel wall. Importantly, diabetic patients suffer from a unique and typically neglected aspect of cardiovascular risk, namely, the striking persistence of intestinally derived apoB-lipoproteins, called `remnants,' in their plasma after each meal. The cause is a defect in hepatic clearance of these harmful particles. A major impediment in this area has been our ignorance regarding pathways for remnant uptake into the liver. A quarter century ago, hepatic uptake of remnants was shown to be independent of LDL receptors. This realization launched a long, difficult search for the responsible molecules. In 1991-1992, seminal work from our laboratory implicated heparan sulfate proteoglycans (HSPGs) in remnant lipoprotein uptake. Each HSPG molecule consists of a protein strand onto which the cell assembles sugar polymers, called heparan sulfate, that we showed could capture lipoproteins. In a major, recent breakthrough, we found that T2DM induces HSPG degradative enzymes in liver. Our central hypothesis is that the identification of compounds that accelerate uptake of atherogenic remnant lipoproteins into liver cells will substantially advance our physiologic understanding while also opening exciting, new avenues for potentially life-saving therapeutics in diabetes. In Aim 1, we propose to develop screens for inducers of hepatocyte uptake of model remnant lipoproteins. Compound screens using whole-cell read-outs are the ideal approach to manage the biologic complexity of HSPG assembly. Aim 1a will automate and optimize our new fluorescent assay for HSPG-mediated uptake of model remnant lipoproteins, in preparation for moderate-throughput screening. Aim 1b will perform titration-based screening of three libraries of diverse, active compounds. In Aim 2, we propose to evaluate hit compounds. Aim 2a will rule out artifacts, establish selectivity for HSPG-mediated uptake, and prioritize compounds. Aim 2b will determine the molecular effects of prioritized compounds. Based on our new data, our favored mechanism is inhibition of HSPG degradative enzymes. Aim 2c will define metabolic responses to enhanced uptake of remnants, to choose potential therapeutic leads. Overall, these proposed Aims will substantially advance our molecular knowledge of remnant lipoprotein clearance, as well as our ability to correct diabetic postprandial dyslipidemia. Our ultimate goal will be to avert the tremendous excess burden of cardiovascular disease in diabetes, to which postprandial dyslipidemia makes a substantial, and potentially avoidable, contribution. PUBLIC HEALTH RELEVANCE: Project relevance to public health Patients with diabetes mellitus suffer from fatal and disabling atherosclerotic cardiovascular disease that results in part from the striking persistence of harmful intestinally derived lipoproteins, called `remnants,' in their plasma after each meal. Based on our seminal work implicating a crucial role for heparan sulfate proteoglycans (HSPGs) in the rapid, healthy disposal of remnant lipoproteins by the liver, we now seek novel compounds to enhance HSPG display by hepatocytes and thereby accelerate the uptake of these harmful lipoproteins. The ultimate goal will be to avert the tremendous excess burden of cardiovascular disease in diabetes.

描述（由申请人提供）：动脉粥样硬化心血管疾病仍然是1型和2型糖尿病患者（T1DM，T2DM）患者的主要死亡原因。动脉粥样硬化是由胆固醇富含胆固醇，载脂蛋白-B（APOB） - 脂蛋白在血管壁内的保留引起的。重要的是，糖尿病患者患心血管风险的独特且通常被忽视的方面，即每顿饭后血浆中无小的衍生的apob脂蛋白（称为“残余）”的惊人持久性。原因是这些有害颗粒的肝清除率缺陷。这一领域的主要障碍是我们对肝脏摄入肝脏的途径的无知。四分之一世纪前，肝摄取残留物被证明与LDL受体无关。这种认识引发了对负责人分子的漫长而艰难的搜索。在1991 - 1992年，我们实验室的开创性工作牵涉到硫酸乙酰肝素蛋白聚糖（HSPGS）中的残留脂蛋白摄取。每个HSPG分子都由一个蛋白质链组成，细胞在该蛋白质链中组装出我们显示的糖聚合物（称为硫酸乙酰肝素）可以捕获脂蛋白。在最近的主要突破中，我们发现T2DM在肝脏中诱导HSPG降解酶。我们的核心假设是，鉴定可以加速摄取动脉粥样硬化性脂蛋白到肝细胞中的化合物，这将大大提高我们的生理理解，同时还为糖尿病中潜在的挽救生命的疗法提供了令人兴奋的新途径。在AIM 1中，我们建议开发用于肝细胞摄取模型残留脂蛋白的筛选。使用全细胞读出的化合物屏幕是管理HSPG组件生物复杂性的理想方法。 AIM 1A将自动化并优化我们的新荧光测定法，以用于HSPG介导的型号残留脂蛋白的摄取，以准备中等通量筛选。 AIM 1B将对三个不同活性化合物的三个库进行基于滴定的筛选。在AIM 2中，我们建议评估命中化合物。 AIM 2A将排除伪影，确定HSPG介导的摄取的选择性，并确定化合物的优先级。 AIM 2B将确定优先化合物的分子效应。基于我们的新数据，我们偏爱的机制是抑制HSPG降解酶。 AIM 2C将定义对增强残留物吸收的代谢反应，以选择潜在的治疗铅。总体而言，这些提出的目标将大大提高我们对残留脂蛋白清除率的分子知识，以及我们纠正糖尿病后餐后血脂异常的能力。我们的最终目标是避免糖尿病中心血管疾病的巨大负担，餐后血脂异常会产生大量且有可能避免的贡献。公共卫生相关性：与糖尿病的公共卫生患者的项目相关性，梅洛蒂斯患有致命的和致残性心血管疾病，部分原因是每顿饭后血浆中有害无亲切衍生的脂蛋白的惊人持久性，称为“残留物”。基于我们的开创性工作，暗示了肝硫酸盐蛋白聚糖（HSPG）在肝脏快速，健康处置残留脂蛋白中至关重要的作用，我们现在寻求新颖的化合物来增强肝素表现出HSPG的表现，从而促进这些有害的脂蛋白的吸收。最终目标是避免糖尿病中心血管疾病的巨大负担。