MECHANISMS OF VASCULAR DISEASE IN DIABETES

糖尿病血管疾病的机制

• 批准号: 8691004
• 负责人: AYAD A JAFFA
• 金额: $ 37.38万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691004
• 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）：糖尿病患者有一系列合并并发症的高风险，包括心血管疾病（CVD）。在2型糖尿病患者中看到的心血管事件的风险增加与这些患者往往在这些患者共存的心血管和代谢疾病的危险因素群有关。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将其确定为高风险，而其他人尽管管理最佳，但其他人仍继续体验心血管事件。尽管这种风险的大部分归因于常规风险因素的存在，例如高血糖，高脂血症，高血压，这种风险的重大负担仍无法解释。炎症介质和生长因子越来越被认为是在动脉粥样硬化发展中起重要作用。因此，该提案的总体目标集中在进行纵向评估，以定义新型生物标记物，结缔组织生长因子（CTGF）的作用和贡献，在2型糖尿病患者中大血管血管和微血管疾病的起始/进展中，并确定在存在微卵皮疾病中CTGF的增加是否会增加Microvascult疾病的增长。我们的初步发现是基于由2型糖尿病患者队列产生的横截面数据，这表明心血管事件的发生与CTGF水平的高度独立联系。我们的结果表明，比没有先前患有心血管疾病的患者的血浆CTGF水平明显高于血浆CTGF的先前糖尿病患者（MI）或冠状动脉疾病（CAD）的水平明显高。我们还发现了这些类型2型糖尿病患者的血浆CTGF和视网膜病变ETDRS评分（AER）之间的循环水平之间的牢固关联。此外，我们的发现表明，与对照小鼠相比，与动脉粥样硬化的APOE - / - 敲除小鼠主动脉诱导了CTGF表达。因此，基于我们生成的初步数据，我们假设较高的循环CTGF反映了高血压，内皮功能障碍和炎症的持续血管损害，并且CTGF水平升高将预测未来的心血管事件的更大风险，以及渐进式视网膜病和肾上腺病和肾上腺病。为了检验我们的假设，我们提出以下特定目的：1）确定血浆CTGF水平是否预测了2型糖尿病患者的未来心血管事件以及渐进性视网膜病和肾病。 2）确定CTGF对糖尿病血管疾病起始和进展的作用和贡献。拟议的研究应将CTGF确立为糖尿病血管疾病的重要危险因素，这将构成定义介入疗法的新靶标的基础。