Dyslipidemia, Lipoic Acid and Diabetic Vascular Complications in Humanized

人源化血脂异常、硫辛酸和糖尿病血管并发症

• 批准号: 7283779
• 负责人: NOBUYO MAEDA
• 金额: $ 35.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-04 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283779
• 关键词: Affect; Antioxidants; Apolipoprotein E; Apolipoproteins B; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Dyslipidemias; Failure; Genes; Genetic; Genetic Polymorphism; Goals; High Density Lipoproteins; Human; Lead; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Messenger RNA; Metabolism; Morbidity - disease rate; Mus; Organ; Oxidative Stress; Patients; Plasma; Play; Production; Protein Isoforms; Protein Overexpression; Relative (related person); Risk; Role; Testing; Thioctic Acid; Tissues; Work; base; density; diabetic; dietary supplements; genetic profiling; genetic risk factor; lipoic acid synthase; mouse model; non-diabetic

DESCRIPTION (provided by applicant): While diabetes mellitus can lead to serious damage to many organs, cardiovascular diseases are the major cause of death and morbidity in diabetic patients. Overall, patients with diabetes have a three to five fold increased risk of coronary artery diseases compared to non-diabetics. Our goal is to use mouse genetics for identifying genetic risk factors for the vascular complications of diabetes and for unraveling underlying mechanisms. Although a significant increase in atherosclerosis by diabetes has been demonstrated in atherogenic mouse models, none of these mouse models faithfully replicates the types of dyslipidemia associated with diabetes in humans. We postulate that this failure is due to differences in the relative levels of plasma low density lipoprotein (LDL) and plasma high density lipoprotein (HDL) that are controlled by genetic differences between the two species and genetic polymorphisms in humans. Thus our first hypothesis is that humanizing genes that are involved in lipoprotein metabolism in mice so that they develop a more human-like diabetic dyslipidemia will cause them to replicate better the cardiovascular problems of human diabetic patients. We will test this hypothesis in Specific Aim 1 by inducing diabetes in mice with humanized apoE of the three isoforms (E2, E3, and E4) and humanized LDL receptor (LDLR), with or without overexpression of human apoB. We predict that this will lead to diabetic dyslipidemia and accelerated atherosclerosis in an apoE isoform dependent manner. Our second hypothesis is that since diabetes is generally acknowledged to induce oxidative stress, genetically determined differences in the levels of endogenous anti-oxidants affect the development of cardiovascular complications,. To test this hypothesis, we propose in Specific Aim 2 to develop a new mouse model with a genetically controlled reduction in the production of the endogenous antioxidant lipoic acid (LA). We will modify the LA synthase (Lias) gene in such a way that the stability of Lias mRNA will be drastically reduced in a tissue specific fashion. Our hypothesis predicts that reduced production of LA will increase the oxidative stress already present in diabetic mice and enhance their development of vascular complications. In Specific Aim 3, we propose to combine human-like diabetic dyslipidemia with genetically reduced antioxidant capacity due to LA deficiency to test our overall thesis that interactions between genetic polymorphic differences affecting lipid profiles and genetic differences affecting endogenous antioxidant levels determine the degree to which diabetes enhances cardiovascular disease.

描述（由申请人提供）： 虽然糖尿病可导致许多器官的严重损害，但心血管疾病是糖尿病患者死亡和发病的主要原因。总体而言，与非糖尿病患者相比，糖尿病患者患冠状动脉疾病的风险增加了三到五倍。我们的目标是利用小鼠遗传学来识别糖尿病血管并发症的遗传风险因素并揭示潜在机制。尽管在动脉粥样硬化小鼠模型中已证明糖尿病会导致动脉粥样硬化显着增加，但这些小鼠模型都没有忠实地复制与人类糖尿病相关的血脂异常类型。我们推测这种失败是由于血浆低密度脂蛋白（LDL）和血浆高密度脂蛋白（HDL）的相对水平存在差异，而这种差异是由两个物种之间的遗传差异和人类遗传多态性控制的。因此，我们的第一个假设是，对小鼠中参与脂蛋白代谢的基因进行人性化，使它们产生更像人类的糖尿病血脂异常，从而使它们更好地复制人类糖尿病患者的心血管问题。我们将在特定目标 1 中测试这一假设，方法是用三种亚型（E2、E3 和 E4）的人源化 apoE 和人源化 LDL 受体 (LDLR)（有或没有人 apoB 过度表达）诱导小鼠患糖尿病。我们预测这将导致糖尿病血脂异常并以apoE亚型依赖性方式加速动脉粥样硬化。我们的第二个假设是，由于人们普遍认为糖尿病会诱发氧化应激，因此基因决定的内源性抗氧化剂水平的差异会影响心血管并发症的发展。为了检验这一假设，我们在具体目标 2 中建议开发一种新的小鼠模型，通过基因控制减少内源性抗氧化剂硫辛酸 (LA) 的产生。我们将修改 LA 合酶 (Lias) 基因，使 Lias mRNA 的稳定性以组织特异性方式大幅降低。我们的假设预测，LA 产生的减少会增加糖尿病小鼠体内已有的氧化应激，并促进其血管并发症的发生。在具体目标 3 中，我们建议将类人糖尿病血脂异常与由于 LA 缺乏而导致的抗氧化能力遗传降低结合起来，以检验我们的总体论点，即影响脂质谱的遗传多态性差异与影响内源性抗氧化剂水平的遗传差异之间的相互作用决定了糖尿病的程度增强心血管疾病。