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）：动脉粥样硬化性心血管疾病仍然是 1 型和 2 型糖尿病（T1DM、T2DM）患者死亡的主要原因。动脉粥样硬化是由于富含胆固醇的载脂蛋白 B (apoB) 脂蛋白滞留在血管壁内而引起的。重要的是，糖尿病患者患有一个独特且通常被忽视的心血管风险，即每餐后血浆中肠道来源的apoB脂蛋白（称为“残留物”）的惊人持续存在。原因是肝脏清除这些有害颗粒的缺陷。该领域的一个主要障碍是我们对肝脏摄取残余物的途径一无所知。四分之一世纪前，肝脏对残余物的摄取被证明与低密度脂蛋白受体无关。这一认识引发了对负责分子的漫长而艰难的探索。 1991-1992 年，我们实验室的开创性工作表明硫酸乙酰肝素蛋白聚糖 (HSPG) 与残余脂蛋白的摄取有关。每个 HSPG 分子都由一条蛋白质链组成，细胞在该蛋白质链上组装糖聚合物，称为硫酸乙酰肝素，我们证明它可以捕获脂蛋白。最近的一项重大突破是，我们发现 T2DM 会诱导肝脏中的 HSPG 降解酶。我们的中心假设是，鉴定出加速致动脉粥样硬化残余脂蛋白进入肝细胞的吸收的化合物将大大推进我们的生理学理解，同时也为糖尿病的潜在挽救生命的治疗开辟令人兴奋的新途径。在目标 1 中，我们建议开发肝细胞摄取模型残余脂蛋白诱导剂的筛选。使用全细胞读数的复合筛选是管理 HSPG 组装生物复杂性的理想方法。目标 1a 将自动化和优化我们用于 HSPG 介导的模型残余脂蛋白摄取的新荧光测定，为中等通量筛选做好准备。目标 1b 将对三个不同活性化合物库进行基于滴定的筛选。在目标 2 中，我们建议评估命中化合物。目标 2a 将排除人为因素，建立 HSPG 介导的摄取的选择性，并优先考虑化合物。目标 2b 将确定优先化合物的分子效应。根据我们的新数据，我们首选的机制是抑制 HSPG 降解酶。目标 2c 将定义对增强残余物吸收的代谢反应，以选择潜在的治疗先导药物。总体而言，这些提出的目标将大大提高我们对残余脂蛋白清除的分子知识，以及我们纠正糖尿病餐后血脂异常的能力。我们的最终目标是避免糖尿病带来的心血管疾病的巨大负担，餐后血脂异常对糖尿病造成巨大的负担，而且可能是可以避免的。公共健康相关性：项目与公共健康的相关性糖尿病患者患有致命性和致残性动脉粥样硬化性心血管疾病，其部分原因是每餐后血浆中有害的肠源性脂蛋白（称为“残余物”）的惊人持续存在。我们的开创性工作表明硫酸乙酰肝素蛋白聚糖 (HSPG) 在肝脏快速、健康地处理残余脂蛋白方面发挥着至关重要的作用，因此我们现在寻求新的化合物来增强肝细胞对 HSPG 的展示，从而加速这些有害脂蛋白的摄取。最终目标是避免糖尿病带来的心血管疾病的巨大负担。