MECHANISMS OF VASCULAR DISEASE IN DIABETES

糖尿病血管疾病的机制

• 批准号: 8895378
• 负责人: AYAD A JAFFA
• 金额: $ 41.05万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895378
• 关键词: Albumins; Aorta; ApoE knockout mouse; Apolipoprotein E; Atherosclerosis; Biological Markers; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Complex; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Data; Databases; Development; Diabetes Mellitus; Diabetic Angiopathies; Disease Outcome; Disease Progression; Dyslipidemias; Endothelial Cells; Event; Excretory function; Functional disorder; Future; Growth Factor; Hyperglycemia; Hyperlipidemia; Hypertension; Individual; Inflammation; Inflammation Mediators; Inflammatory; Kidney Diseases; Knockout Mice; Knowledge; Lead; Leptin; Light; Link; Longitudinal Studies; Measurement; Measures; Metabolic; Metabolic Diseases; Microvascular Dysfunction; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Patients; Plasma; Play; Production; Recording of previous events; Research; Retinal Diseases; Risk; Risk Assessment; Risk Factors; Risk Marker; Role; Sampling; Signal Transduction; Testing; Time; United States Department of Veterans Affairs; Vascular Diseases; base; cardiovascular risk factor; cohort; connective tissue growth factor; diabetic; diabetic patient; endothelial dysfunction; evidence base; experience; glycemic control; high risk; in vivo; indexing; inflammatory marker; insight; kidney vascular structure; macrovascular disease; mouse model; novel; novel therapeutic intervention; prevent; public health relevance; tool; treatment strategy; trend

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.

描述（由申请人提供）：糖尿病患者发生一系列合并症的风险很高，包括心血管疾病（CVD）。 2 型糖尿病患者心血管事件风险增加与这些患者中往往共存的一系列心血管和代谢紊乱危险因素有关。尽管成功实施了基于证据的策略，但许多人在第一次事件发生之前并未被识别为高风险，而其他人尽管采取了最佳管理，仍继续经历心血管事件。虽然这种风险大部分归因于传统风险因素的存在，例如高血糖、高脂血症、高血压，但这种风险的巨大负担仍然无法解释。人们越来越认识到炎症介质和生长因子在动脉粥样硬化的发展中发挥着重要作用。因此，该提案的总体目标侧重于进行纵向评估，以确定新型生物标志物结缔组织生长因子（CTGF）在2型糖尿病受试者大血管和微血管疾病的发生/进展中的作用和贡献，并确定在存在微血管疾病的情况下CTGF的增加是否可以预测大血管疾病的发展。我们的初步研究结果基于 2 型糖尿病患者队列的横断面数据，表明心血管事件的发生与 CTGF 水平升高独立相关。我们的结果表明，既往有心肌梗塞（MI）或冠状动脉疾病（CAD）病史的糖尿病患者的血浆CTGF水平显着高于先前没有心血管事件的患者。我们还发现，在这些 2 型糖尿病受试者中，血浆 CTGF 的循环水平与视网膜病变 ETDRS 评分以及白蛋白排泄率 (AER) 之间存在密切关联。此外，我们的研究结果表明，与对照小鼠相比，患有动脉粥样硬化的 ApoE-/- 敲除小鼠的主动脉中诱导了 CTGF 表达。因此，根据我们生成的初步数据，我们假设循环中 CTGF 水平较高反映了高血压、内皮功能障碍和炎症造成的持续血管损伤，并且 CTGF 水平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风险更大。为了检验我们的假设，我们提出以下具体目标：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)确定CTGF对糖尿病血管疾病的发生和进展的作用和贡献。拟议的研究应将 CTGF 确定为糖尿病血管疾病的病理学重要危险因素，这将成为确定介入治疗新目标的基础。