PORCINE MODELS OF CORONARY ARTERY DISEASE IN DIABETES

描述(改编自申请人的摘要)： 这个应用是通过内分泌、代谢、 和心血管标准，以确定它们是否适合 人类糖尿病中的冠状动脉疾病(CAD)。这个项目不会落空 只为了一个NIH研究所的绝对利益，因为这些 是糖尿病(NIDDK)和血管生物学(NHLBI)的综合研究。 实验设计为研究高脂饲料诱导的猪 血脂异常合并四氧嘧啶糖尿病。猪的模型 能够严格控制这些变量、CAD的侵入性措施，以及 为体外组织和细胞研究提供充足的血浆和动脉。 在数周的治疗期间连续监测猪的能力 促进糖尿病患者CAD发展的研究，而糖尿病尚未得到 在广泛使用的啮齿动物和转基因小鼠模型中是可能的。具体的 目的是：1)描述糖尿病的内分泌和代谢指标。一个 将开发对猪更实用的胰岛素敏感性测试 以确定这些猪模型最能代表哪些类型的糖尿病；2) 描述糖尿病的血脂异常。传统的和“非传统的”脂质， 包括氧化型低密度脂蛋白、糖化低密度脂蛋白和 营养抗氧化剂将描述糖尿病“风险”的独特特征 3)决定糖尿病患者病情发展的时间进程 与体外血管内超声(IVUS)相关的“危险因素谱” 功能CAD和结构CAD的测量。侵入性静脉内超声检查 冠状动脉导管动脉粥样硬化、管径和多普勒血流测量 Flow将区分微血管和微血管CAD；4) 描述冠状动脉功能CAD和结构CAD的范围 体外培养。脂肪条纹测量和体外收缩和 血管活性物质对冠脉环的内皮依赖性松弛作用 提供CAD的其他端点；5)将平滑肌和内皮细胞关联起来 钙与冠心病。申请者将决定是否单细胞钙 体内和体外冠状动脉血管反应性的平行变化； 描述冠状动脉粥样硬化术后再狭窄的程度。自.以来 糖尿病患者气囊扩张后再狭窄的发生率高2倍。 血管成形术后，申请者将决定预后是否较好 做动脉粥样硬化切除术。猪模型的发展提供了 申请人未来几乎所有学习的基本基础， 包括药物治疗、运动训练和详细研究 糖尿病合并冠心病的细胞/分子机制。

DESCRIPTION (Adapted from the applicant's abstract): The central purpose of this application is to characterize porcine models by endocrine, metabolic, and cardiovascular criteria to determine if they are suitable models of coronary artery disease (CAD) in human diabetes. This project does not fall in the categorical interest of only a single NIH Institute, because these are integrated studies of diabetes (NIDDK) and vascular biology (NHLBI). The experimental design is to study pigs having high fat diet-induced dyslipidemia combined with alloxan-induced diabetes. The porcine model enables tight control of these variables, invasive measures of CAD, and provides ample plasma and arteries for in vitro tissue and cell studies. The ability to monitor swine serially over many weeks of treatment facilitates study of CAD development in diabetes, which has not been possible in widely used rodent and transgenic mouse models. The Specific Aims are: 1) Describe the endocrine and metabolic indices of diabetes. An insulin sensitivity test that is more practical for swine will be developed to determine which types of diabetes these porcine models best represent; 2) Describe diabetic dyslipidemia. Traditional and "nontraditional" lipids, including oxidized low density lipoprotein (LDL), glycated LDL, and nutritional antioxidants will describe unique features of a diabetic "risk factor profile;" 3) Determine the time course of progression of the diabetic "risk factor profile" relative to in vitro intravascular ultrasound (IVUS) measures of functional CAD and structural CAD. Invasive IVUS measures of conduit artery atheroma, diameter, and Doppler flow measures of coronary flow will distinguish between microvascular and microvascular CAD; 4) Describe the extent of coronary artery functional CAD and structural CAD in vitro. Fatty streak measures and in vitro contraction and endothelium-dependent relaxation of coronary rings to vasoactive agents will provide other endpoints of CAD; 5) Correlate smooth muscle and endothelial calcium with CAD. The applicants will determine whether single cell calcium alterations parallel in vivo and in vitro coronary vasoreactivity; and 6) Describe the extent of restenosis after coronary atherectomy. Since diabetics have a 2-fold higher incidence of restenosis after balloon angioplasty, the applicants will determine whether the prognosis is better with atherectomy. The development of porcine models provides the fundamental basis for virtually all of the applicant's future studies, including pharmacotherapy, exercise training, and detailed studies of cellular/molecular mechanisms of CAD in diabetes.