Animal Models of Diabetic Vascular Disease

糖尿病血管疾病的动物模型

• 批准号: 6786756
• 负责人: JAN Leslie BRESLOW
• 金额: $ 90.99万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6786756
• 关键词: apolipoprotein B; atherosclerosis; biotechnology; cooperative study; diabetes mellitus; diabetic angiopathy; disease /disorder model; gene induction /repression; genetically modified animals; high density lipoproteins; insulin sensitivity /resistance; laboratory mouse; lipid disorder; low density lipoprotein; model design /development; obesity; pancreatic islets; pathologic process; restenosis; transfection

Since the mayor cause of morbidity and mortality in diabetics is macrovascular disease, we propose creating mouse models in which diabetes worsens macrovascular disease. These models will be of great use for studies of pathophysiology and to design new therapies. To produce such models, we have assembled a multidisciplinary team with expertise in mouse models of diabetes and dyslipidemia and in the evaluation of atherosclerosis progression, atherosclerosis regression/remodeling and injury/restenosis. We propose modern genetic approaches to generate diabetic mouse models in which hyperglycemia can be induced by compromising pancreatic (beta-cell function. This will be accomplished through the conditional expression of dominant-negative mutant forms of HNF-1 alpha or HNF-4 alpha or through the inactivation of HNF-1 beta using beta-cell specific promoters and inducible recombinases in transgenic mice. Mice in which hyperglycemia can be induced will be crossed with genetically manipulated mice that have defects of insulin resistance and /or obesity. This aim, in a novel way, will establish diabetic animal models that recapitulate the clinical history of the most common form of diabetes, type II, which is characterized by a variable period of insulin resistance/obesity (pre-diabetic state) followed by P-cell decompensation and the development of overt diabetes. A second challenge will be to mimic in the mouse the diabetic dyslipidemia phenotype, which is characterized by increased triglycerides, small dense LDL and decreased HDL cholesterol. Since we have already shown that this is insufficient to cause atherosclerosis in the mouse, we will also breed in traits to raise the levels of LDL cholesterol. To accomplish this we will use human apo CIII and cholesterol ester transfer, protein transgenes and either the human apo B transgene or the LDL receptor knockout trait. Our strategy will be to cross diabetic models with the diabetic dyslipidemia models to establish new models in which diabetes worsens macrovascular disease, as measured by atherosclerosis progression, regression/remodeling, and/or injury/restenosis. We will then use new genetic technology to combine the various required alleles to make a diabetogenic- macrovascular disease model that is easy to breed and transfer to other investigators.

由于糖尿病患者发病和死亡的主要原因是大血管疾病，因此我们建议创建糖尿病使大血管疾病恶化的小鼠模型。这些模型对于病理生理学研究和设计新疗法将非常有用。为了制作这样的模型，我们组建了一个多学科团队，他们在糖尿病和血脂异常小鼠模型以及动脉粥样硬化进展、动脉粥样硬化消退/重塑和损伤/再狭窄评估方面拥有专业知识。我们提出现代遗传方法来产生糖尿病小鼠模型，在该模型中，可以通过损害胰腺（β-细胞功能）来诱导高血糖。这将通过 HNF-1 α 或 HNF-4 α 或 HNF-4 α 或 HNF-4 显性失活突变形式的条件表达来实现通过在转基因小鼠中使用β细胞特异性启动子和诱导重组酶灭活HNF-1β，可以诱导高血糖的小鼠将与经过基因改造的小鼠杂交。该目标将以一种新颖的方式建立糖尿病动物模型，以概括最常见的 II 型糖尿病的临床病史，其特点是胰岛素抵抗/肥胖的不同时期。 （糖尿病前期状态），然后是 P 细胞失代偿和明显糖尿病的发展。第二个挑战是在小鼠中模拟糖尿病血脂异常表型，其特征是甘油三酯增加、小密度低密度脂蛋白减少和减少。高密度脂蛋白胆固醇。由于我们已经证明这不足以引起小鼠动脉粥样硬化，因此我们还将培育提高低密度脂蛋白胆固醇水平的性状。为了实现这一目标，我们将使用人类载脂蛋白 CIII 和胆固醇酯转移、蛋白质转基因以及人类载脂蛋白 B 转基因或 LDL 受体敲除特性。我们的策略是将糖尿病模型与糖尿病血脂异常模型交叉，建立新模型，其中糖尿病恶化大血管疾病，通过动脉粥样硬化进展、消退/重塑和/或损伤/再狭窄来衡量。然后，我们将使用新的遗传技术来组合各种所需的等位基因，以制作易于培育和转移给其他研究人员的糖尿病大血管疾病模型。