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: 7664398
• 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/7664398
• 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; Relative (related person); Risk; Role; Testing; Thioctic Acid; Tissues; Work; base; density; diabetic; diabetic patient; dietary supplements; genetic profiling; genetic risk factor; lipoic acid synthase; mouse model; non-diabetic; overexpression

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）： 尽管糖尿病可能会对许多器官造成严重损害，但心血管疾病是糖尿病患者的死亡和发病率的主要原因。总体而言，与非糖尿病患者相比，患有糖尿病患者的冠状动脉疾病风险增加了三到五。我们的目标是使用小鼠遗传学来鉴定糖尿病血管并发症和解散潜在机制的遗传危险因素。尽管在动脉粥样硬化小鼠模型中已经证明了糖尿病动脉粥样硬化的显着增加，但这些小鼠模型均未忠实地复制与人类中与糖尿病相关的血脂异常的类型。我们假设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）的相对水平的差异所致，这些脂蛋白（HDL）受到人类两种物种和遗传多态性之间的遗传差异的控制。因此，我们的第一个假设是，小鼠脂蛋白代谢涉及的人性化基因，因此它们会产生更类似人类的糖尿病性血脂异常，这会导致它们更好地复制人类糖尿病患者的心血管问题。我们将通过在三种同工型（E2，E3和E4）和人源化的LDL受体（LDLR）中诱导人源化APOE的小鼠中的糖尿病在特定的目标1中检验这一假设，并具有人apob过度表达。我们预测，这将导致糖尿病血脂异常，并以APOE同工型依赖性方式加速动脉粥样硬化。我们的第二个假设是，由于通常承认糖尿病会诱导氧化应激，因此内源性抗氧化剂水平的遗传确定的差异会影响心血管并发症的发展。为了检验这一假设，我们在特定的目标2中提出了一种新的小鼠模型，该模型具有遗传控制的内源性抗氧化剂脂肪酸（LA）的遗传控制。我们将以某种方式修改LA合酶（LIAS）基因，以使LIAMRNA的稳定性大大降低。我们的假设预测，LA的产生减少将增加糖尿病小鼠中已经存在的氧化应激，并增强其血管并发症的发展。在特定的目标3中，我们建议将类似人类的糖尿病血脂异常与遗传降低的抗氧化能力相结合，因为LA缺乏症，以测试我们的整体论点，即影响脂质差异的遗传多态性差异与影响脂肪差异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确定糖尿病的程度，从而确定了糖尿病的程度。