Markers and Mechanisms of Vascular Disease in Diabetes

描述(由申请人提供) 血管疾病是患者并发症和死亡的主要原因 患有糖尿病。风险标记物和潜在机制尚未完全 阐明，并可能与非糖尿病患者不同。这个 该计划项目的统一主题是高血糖和胰岛素 抗药性改变了许多生物过程，这些过程以恶性的方式相互作用 加速动脉粥样硬化形成的周期，因此是主要的潜在风险 导致血管疾病的因素。总体目标是定义这些 独特的过程，并阐明潜在的生化、代谢和 糖尿病血管病变并发症的遗传决定因素。超过了 在过去的4年里，我们与DCCT/EDIC研究小组合作，并已 对I型血管疾病的发病机制进行了新的观察 糖尿病。这项工作将我们的研究集中在特定的致病过程上。 我们还将纳入来自退伍军人管理局合作社的2型糖尿病队列 研究，“血糖控制和2型糖尿病并发症”，高 血管疾病事件发生率。这些协作提供了独特的 有机会解决动脉粥样硬化加速形成的发病机制 两种主要类型的糖尿病，并将大大增加科学知识 这将在这些世界级前瞻性试验的进行中获得。 该计划项目有4个项目和3个核心。项目1将评估 脂蛋白、糖氧化应激和炎症作为危险因素 涉及1型和2型糖尿病患者和培养细胞系统的研究。 根据初步数据，核磁共振脂蛋白亚类分布的变化 将会被强调。项目2将阐明 血管炎症、脂蛋白修饰和自身免疫 疾病风险。这些新颖的概念也是基于令人兴奋的初步 关于低密度脂蛋白-抗体复合体的数据。项目3将追求有趣 初步数据和确定激肽释放酶-激肽系统在 血管疾病并发症，对有丝分裂和基质的影响 制作。项目5将评估胰岛素抵抗综合征的作用 脂肪细胞分泌的新因子在糖尿病的病理生理学中的作用 生化危险因素和心血管并发症。核心包括一个 生物统计学和流行病学将与 试验数据协调中心，以及分子和统计遗传学核心。 在科学和后勤方面的项目之间存在着真正的协同效应 级别。计划项目设计允许多学科之间的互动 研究同一群人的调查人员，这将定义 多个病理过程在动脉壁水平上相互作用 促进动脉粥样硬化。

DESCRIPTION (provided by applicant) Vascular Disease is the leading cause of complications and death in patients with diabetes. Risk markers and underlying mechanisms have not been fully elucidated, and may differ from those in non-diabetic individuals. The unifying theme for the Program Project is that hyperglycemia and insulin resistance alter a number of biological processes which interact in vicious cycles to accelerate atherogenesis and are consequently major underlying risk factors for vascular disease. The overall objectives are to define these unique processes and to elucidate underlying biochemical, metabolic, and genetic determinants of vascular disease complications in diabetes. Over the past 4 years, we have collaborated with the DCCT/EDIC Study Group, and have made novel observations regarding vascular disease pathogenesis in Type I Diabetes. This work has focused our studies on specific pathogenic processes. We will also incorporate a Type 2 Diabetes cohort from the VA Cooperative Study, "Glycemic Control and the Complications of Diabetes, Type 2", with high vascular disease event rates. These collaborations provide a unique opportunity to address the pathogenesis of accelerated atherogenesis in the two main types of diabetes, and will greatly augment the scientific knowledge that will be gained in the conduct of these world-class prospective trials. The Program Project has 4 projects and 3 cores. Project 1 will assess lipoproteins, glycoxidative stress, and inflammation as risk factors in studies involving Type 1 and 2 Diabetes patients and cultured cell systems. Based on preliminary data, changes in the NMR lipoprotein subclass profile will be emphasized. Project 2 will elucidate interactions between inflammation, modifications of lipoproteins, and autoimmunity in vascular disease risk. These novel concepts are also based upon exciting preliminary data pertaining to LDL-antibody complexes. Project 3 will pursue interesting preliminary data and define the role of the kallikrein-kinin system in vascular disease complications, with effects on mitogenesis and matrix production. Project 5 will assess the role of the Insulin Resistance Syndrome and novel factors secreted from adipocytes in the pathophysiology of biochemical risk factors and cardiovascular complications. Cores include an Biostatistics and Epidemiology which will link with the trials data coordinating centers, and Molecular and Statistical Genetics Core. There is true synergism among the projects at both scientific and logistical levels. The Program Project design allows for interactions among multi-disciplinary investigators studying the same cohorts, which will define how multiple pathological processes interact at the level of the arterial wall to promote atherosclerosis.