MECHANISMS OF VASCULAR DISEASE IN DIABETES

描述(申请人提供)：糖尿病患者有一系列并发症的高风险，包括心血管疾病(CVD)。2型糖尿病患者心血管事件风险的增加与心血管和代谢紊乱的一系列危险因素有关，这些因素往往在这些患者中共存。尽管成功地实施了基于证据的策略，但许多人在第一次事件之前并未被确定为高风险，其他人尽管进行了最佳管理，但仍继续经历心血管事件。虽然这种风险在很大程度上可归因于传统风险因素的存在，如高血糖、高脂血症、高血压，但这种风险的重大负担仍然无法解释。炎症介质和生长因子在动脉粥样硬化的发生发展中发挥着重要作用。因此，这项建议的总体目标是进行纵向评估，以确定结缔组织生长因子(CTGF)这一新的生物标记物在2型糖尿病患者大血管和微血管疾病的发生/发展中的作用和贡献，并确定在存在微血管疾病的情况下CTGF增加是否会预测大血管疾病的发展。我们的初步发现基于一组2型糖尿病患者的横断面数据，表明心血管事件的发生与CTGF水平的升高独立相关。我们的结果表明，有心肌梗死(MI)或冠心病(CAD)病史的糖尿病患者的血浆CTGF水平显著高于无心血管事件史的患者。我们还发现，在这些2型糖尿病受试者中，循环血浆CTGF水平与视网膜病变、ETDRS评分以及白蛋白排泄率(AER)之间存在很强的相关性。此外，我们的研究结果表明，与对照组相比，ApoE/-基因敲除的动脉粥样硬化小鼠的主动脉中CTGF的表达被诱导。因此，根据我们生成的初步数据，我们假设循环中CTGF水平的升高反映了高血压、内皮功能障碍和炎症造成的持续血管损害，并且CTGF水平的升高将预测未来心血管事件以及进行性视网膜病变和肾病的更大风险。为了验证我们的假设，我们提出了以下具体目标：1)确定血浆CTGF水平是否可以预测2型糖尿病患者未来的心血管事件以及进行性视网膜病变和肾病。2)明确CTGF在糖尿病血管病变发生发展中的作用和贡献。拟议的研究应将CTGF确立为糖尿病血管疾病的一个重要的病理危险因素，这将为确定介入治疗的新靶点奠定基础。

DESCRIPTION (provided by applicant): Diabetic patients are at high risk of a range of comorbid complications, including cardiovascular disease (CVD). The increased risk of cardiovascular events seen in patients with type 2 diabetes is associated with a cluster of risk factors for cardiovascular and metabolic disorders that tend to coexists in these patients. Despite successful implementation of evidence based strategies, many individuals are not identified as high risk before their first event and others continue to experience cardiovascular events despite optimal management. While much of this risk is attributable to the presence of conventional risk factors, such as hyperglycemia, hyperlipidemia, hypertension, a substantial burden of this risk remains unexplained. Inflammatory mediators and growth factors are increasingly recognized as playing important roles in the development of atherosclerosis. Therefore the overall objective of this proposal focuses on performing longitudinal assessment to define the role and contribution of a novel biomarker, connective tissue growth factor (CTGF), in the initiation/ progression of macrovascular and microvascular disease in subjects with type 2 diabetes and to determine whether increases in CTGF in the presence of microvascular disease will predict development of macrovascular disease. Our preliminary findings, based on cross-sectional data generated from a cohort of type 2 diabetic patients, suggest that the occurrence of cardiovascular events is independently linked to elevations in CTGF level. Our results demonstrate that diabetic patients with a prior history of myocardial infarction (MI) or coronary artery disease (CAD) have significantly higher levels of plasma CTGF than patients who have not had a prior cardiovascular event. We also uncovered a strong association between circulating levels of plasma CTGF and retinopathy ETDRS scores as well as albumin excretion rate (AER) in these type 2 diabetic subjects. In addition, our findings demonstrate that CTGF expression is induced in aorta of ApoE-/- knockout mice with atherosclerosis compared to control mice. Therefore, based on the preliminary data we generated, we hypothesize that higher levels of circulating CTGF reflect ongoing vascular damage from hypertension, endothelial dysfunction and inflammation, and that elevated CTGF levels will predict greater risk for future cardiovascular events and progressive retinopathy and nephropathy. To test our hypothesis we propose the following specific aims: 1) Determine whether plasma CTGF levels predict future cardiovascular events and progressive retinopathy and nephropathy in individuals with type 2 diabetes. 2) Determine the role and contribution of CTGF to the initiation and progression of diabetic vascular disease. The proposed studies should establish CTGF as a pathologically-important risk factor for diabetic vascular disease that will form the basis for defining new targets for interventional therapy.