Hyperglycemia, Aldose Reductase and Murine Atherosclerosis

高血糖、醛糖还原酶和小鼠动脉粥样硬化

基本信息

批准号：
7795884
负责人：
Ira J Goldberg
金额：
$ 47.01万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7795884
关键词：
Abbreviations Acceleration Address Adhesives Affect Aldehyde Reductase Aldolase B Animal Model Aorta Apolipoprotein E Apoptosis Apoptotic Arterial Fatty Streak Arteries Atherosclerosis Biochemical Process Biological Assay Biological Models Biology Blindness Blood Glucose Blood Vessels Bone Marrow Bone Marrow Transplantation Breslow Thickness CD36 gene CETP gene Candidate Disease Gene Cause of Death Cells Cholesterol Cholesterol Ester Transfer Proteins Citric Acid Cycle Clinical Clinical Research Collaborations Complication Complications of Diabetes Mellitus Controlled Study Coronary heart disease Cross-Sectional Studies Cytoskeleton Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic macrovascular disease Diabetic mouse Diet Dietary Intervention Disease Dyslipidemias Endothelial Cells Enzymes Face Failure Fatty acid glycerol esters Fructose Funding Funding Mechanisms Gene Expression Genes Genetic Genetic Models Glucose Goals Grant Heart High Density Lipoprotein Cholesterol Histocompatibility Antigens Human Hyperglycemia Hyperlipidemia Hypertension In Vitro Inflammation Inflammatory Insulin Insulin Resistance Islet Cell Kidney Failure Knock-out Knockout Mice L-Iditol 2-Dehydrogenase Laboratories Lead Leptin deficiency Lesion Lipids Lipoproteins Low Density Lipoprotein Receptor Maps Mediating Methods Modeling Morphology Mus Mutation Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Patients Peripheral Vascular Diseases Peritoneal Macrophages Phenotype Phosphotransferases Play Prevention Prevention therapy Process Production Public Health RNA Interference Reactive Oxygen Species Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Role Series Signal Transduction Sorbitol Streptozocin Stroke Tail Techniques Technology Testing Time Toxic effect Transgenes Transgenic Mice Transgenic Organisms United States National Institutes of Health animal model development cytokine diabetic gene therapy in vivo laser capture microdissection lipoprotein lipase macrophage macrovascular disease meetings model development mouse model mutant mouse model overexpression oxidation promoter receptor research study response reverse cholesterol transport scavenger receptor therapeutic target tissue culture uptake

项目摘要

Although diabetes mellitus is associated with the development of more atherosclerosis, the reasons for this are not entirely understood. Efforts during the past decade to develop animal models of diabetic macrovascular disease were confounded by the development of hyperlipidemia in many diabetic mice or the failure of hyperglycemia alone to accelerate atherosclerosis. We hypothesized that mice were deficient in a gene required to allow the toxic effects of hyperglycemia on arteries. Mice are relatively deficient in aldose reductase (AR), the enzyme that converts glucose to sorbitol. We discovered that LDL receptor knockout mice (Ldlr-/-) made diabetic with streptozotocin (STZ) treatment have accelerated, atherosclerosis when a transgene expressing human AR (hAR) is present. Moreover, heterozygous Ldlr-/- mice also have greater lesion size with STZ-treatment. This grant proposes to study the relationship between AR expression and murine atherosclerosis. The specfic aims are as follows: Aim 1. To determine the effects of hAR expression on macrovascular disease in diabetic models. Dietary and genetic models of insulin deficiency and insulin resistance will be crossed onto the Ldlr-/- background with and without hAR expression. Aim 2. To assess whether AR over-expression in endothelial cells or macrophages mediates hyperglycemia-induced atherosclerosis. These experiments will employ transplantion of bone marrow and production of new lines of transgenic AR expressing mice. Aim 3. To determine whether AR expression in endothelial cells and/or macrophages affects inflammatory processes in the setting of hyperglycemia. Tissue culture experiments will explore pathways relating hAR expression to inflammation and cellular cholesterol uptake. This information will then be used to study AR effects in vivo. These studies will, we expect, illustrate a genetic intervention that leads to reproducible diabetes-mediated acceleration of atherosclerosis in mice. This is significant because it will provide for a model to study this complication and suggest a therapeutic target for prevention of diabetic macrovascular disease.

尽管糖尿病与更多动脉粥样硬化的发生有关，但其原因没有完全理解。过去十年开发糖尿病动物模型的努力大血管疾病与许多糖尿病小鼠或小鼠中高脂血症的发展相混淆。单独使用高血糖无法加速动脉粥样硬化。我们假设小鼠缺乏一种允许高血糖对动脉产生毒性作用所需的基因。小鼠相对缺乏醛糖还原酶 (AR)，将葡萄糖转化为山梨醇的酶。我们发现 LDL 受体敲除用链脲佐菌素 (STZ) 治疗患糖尿病的小鼠 (Ldlr-/-) 会加速动脉粥样硬化存在表达人 AR (hAR) 的转基因。此外，杂合的 Ldlr-/- 小鼠也具有更大的 STZ 治疗后的病变大小。该资助计划研究 AR 表达与小鼠动脉粥样硬化。具体目的如下：目的 1. 确定 hAR 表达的影响糖尿病模型中大血管疾病的研究。胰岛素缺乏和胰岛素的饮食和遗传模型抗性将交叉到具有或不具有 hAR 表达的 Ldlr-/- 背景上。目标 2. 评估内皮细胞或巨噬细胞中AR过度表达是否介导高血糖诱导动脉粥样硬化。这些实验将采用骨髓移植和新细胞系的生产表达AR的转基因小鼠。目标 3. 确定 AR 是否在内皮细胞中表达和/或巨噬细胞影响高血糖情况下的炎症过程。组织培养实验将探索 hAR 表达与炎症和细胞胆固醇摄取的相关途径。此信息然后将用于研究 AR 体内效果。我们期望这些研究将说明基因干预这导致小鼠体内糖尿病介导的动脉粥样硬化可重复加速。这意义重大因为它将提供一个模型来研究这种并发症并提出预防的治疗目标糖尿病大血管疾病。