Lipoproteins and PEDF in the Vascular Complications of Diabetes

描述(申请人提供)：微血管和大血管疾病是糖尿病发病率和过早死亡的主要原因。我们的基本假设是，血管损伤是由血脂异常、炎症和氧化应激等相互关联的过程促进的，这些过程可能部分是由生长因子失衡介导的。“糖尿病血管并发症中的脂蛋白和PEDF”，以1996年以来与DCCT/EDIC研究组和2001年以来VADT研究组的互动以及相关血管细胞培养工作收集的数据为基础。首先，(在队列研究中)我们将确定核磁共振定义的脂蛋白亚类作为糖尿病大血管和微血管并发症的标志物的作用。脂蛋白亚类将横向和纵向与并发症状态相关，并与存在的(同时)血脂异常、炎症、氧化应激和其他内皮功能障碍和胰岛素抵抗的详细测量数据相关。其次，我们将确定循环色素上皮衍生因子(PEDF)在糖尿病血管并发症中的相关性和可能的致病作用。PEDF具有抗炎、抗氧化和抗血管生成作用，在糖尿病视网膜病变和肾病中起保护作用，但在动脉粥样硬化中可能有不同的作用和意义。在我们的人类血管细胞培养工作中，我们将使用相关刺激(未经修饰和糖化氧化的低密度脂蛋白和PEDF)来评估炎症、细胞凋亡/增殖、细胞因子释放、血管生成反应和NF-8B信号转导。具体目的有三：目的1：确定和比较核磁共振定义的脂蛋白亚类与1型和2型糖尿病患者心血管疾病、视网膜病变和肾病的关系；目的2：确定血清PEDF水平与并发症和其他危险标志物的关系；目的3：比较脂蛋白和PEDF对培养的人单核细胞/巨噬细胞、主动脉内皮细胞、平滑肌细胞和肾系膜细胞的影响。风险标记物措施将与DCCT/EDIC和VADT队列中新的“硬”心血管结局和微血管疾病进展相关。最终的目标是从机制上理解糖尿病的血管损伤，这将导致更好的预测和治疗策略。与公共卫生相关：7.项目叙述糖尿病及其并发症(过早心脏病发作和中风、截肢、肾衰竭、失明和神经损伤)在我国和世界流行，迫切需要有效的战略来预测、预防和治疗这些并发症。更好地了解糖尿病的血管并发症是最优先的研究目标，以便制定有效的治疗和预防策略。这项工作涉及与联邦政府资助的两项关于1型和2型糖尿病的大型前瞻性研究的持续合作，解决了糖尿病慢性血管并发症的标志和机制。

DESCRIPTION (provided by applicant): Micro- and macrovascular disease are major causes of morbidity and premature mortality in diabetes mellitus. Our underlying hypothesis is that vascular damage is promoted by the inter-related proceses of dyslipoproteinemia, inflammation, and oxidative stress, which may in part be mediated by growth factor imbalance. "Lipoproteins and PEDF in the Vascular Complications of Diabetes", builds on data collected from interactions with the DCCT/EDIC Study Group since 1996, and the VADT Study Group since 2001, and from related vascular cell culture work. First, (in the cohort studies) we will define the role of lipoprotein subclasses defined by nuclear magnetic resonance (NMR) as markers for macro- and microvascular complications of diabetes. Lipoprotein subclasses will be related cross-sectionally and longitudinally to complication status, and to existent (concurrent) data of detailed measures of dyslipoproteinemia, inflammation, oxidative stress, and other measures of endothelial dysfunction and insulin resistance. Second, we will define associations and possible pathogenic role of circulating Pigment Epithelial Derived Factor (PEDF) in the vascular complications of diabetes. PEDF, which has anti-inflammatory, anti-oxidant and anti-angiogenic actions is implicated (as a protective factor) in diabetic retinopathy and nephropathy, but may have different actions and significance in atherosclerosis. In our human vascular cell culture work, we will employ relevant stimuli (unmodified and glycated and oxidized Low Density Lipoprotein and PEDF) to evaluate inflammation, apoptosis/proliferation, cytokine release, angiogenic responses, and NF-8B signaling There are three Specific Aims: Aim 1: To determine and compare the relationships between NMR-defined lipoprotein subclasses and cardiovascular disease, retinopathy and nephropathy in Type 1 and Type 2 diabetes; Aim 2: To determine the relationship between serum PEDF levels and complications and other risk markers; Aim 3: To compare effects of lipoproteins and of PEDF on cultured human monocyte/macrophages, aortic endothelial, smooth muscle cells and renal mesangial cells. Risk marker measures will be related to new "hard" CVD outcomes and microvascular disease progression in the DCCT/EDIC and VADT cohorts. The eventual goal is a mechanistic understanding of vascular damage in diabetes that will result in better predictive and therapeutic strategies. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Diabetes and its complications (premature heart attacks and strokes, amputations, kidney failure, blindness, and nerve damage) are epidemic in our nation and the world, and effective strategies to predict, prevent, and treat these complications are urgently needed. A better understanding of the vascular complications of diabetes is a research goal of the highest priority so that effective treatments and preventive strategies may be developed. This work, which involves ongoing collaboration with two large federally funded prospective studies of Type 1 and of Type 2 diabetes, addresses markers and mechanisms for the chronic vascular complications of diabetes.