LIPOPROTEINS, CTGF AND DIABETIC VASCULAR & RENAL DISEASE

脂蛋白、CTGF 和糖尿病血管

• 批准号: 7762784
• 负责人: AYAD A JAFFA
• 金额: $ 35.44万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762784
• 关键词: Affect; Albumins; Albuminuria; Basic Science; Binding; Biological Markers; Blood Pressure; Blood Vessels; Clinical; Collagen; Confidence Intervals; Data; Deposition; Development; Diabetes Mellitus; Diabetic Angiopathies; Endothelial Cells; Excretory function; Generations; Genetic Polymorphism; Growth Factor Gene; Human; Hypertension; Inpatients; Insulin-Dependent Diabetes Mellitus; Kidney Diseases; Knowledge; LDL Cholesterol Lipoproteins; Link; Lipids; Lipoproteins; Low-Density Lipoproteins; MAP Kinase Gene; Measurement; Measures; Mediating; Microalbuminuria; Modeling; Outcome; Pathway interactions; Patients; Plasma; Play; Process; Production; Promoter Regions; Proteins; Regression Analysis; Relative (related person); Relative Risks; Research; Research Personnel; Risk Factors; Role; Sampling; Sclerosis; Second Messenger Systems; Signal Transduction; Surrogate Markers; Testing; Thick; Time; Transforming Growth Factors; Vascular Diseases; autocrine; base; cardiovascular risk factor; cohort; connective tissue growth factor; diabetic; diabetic patient; disorder risk; genetic variant; inorganic phosphate; intima media; kidney cell; kidney vascular structure; macroalbuminuria; macrovascular disease; member; mesangial cell; novel; oxidized low density lipoprotein; programs; promoter; response; second messenger; sphingosine 1-phosphate; sphingosine kinase; trend; type I diabetic; urinary

The risk factors that contribute to the development of vascular disease in diabetes are not fully defined. The overall objective of this proposal is to elucidate the cellular and molecular interactions between lipoproteins and connective tissue growth factor (CTGF) and their contributions to the development of vascular disease in type 1 diabetes, and to elucidate the underlying mechanisms involved in this process. Our findings in type 1 diabetic patients, demonstrate for the first time, an association between CTGF and vascular disease risk factors such as, hypertension, microalbuminuria and elevated lipids. In addition, we identified a novel polymorphism in the promoter region of the CTGF gene that associates with increased albuminuria. The relative risk to develop microalbuminuria in patients with the polymorphism is 3 times higher than patients without the polymorphism. At a cellular level, our data demonstrates that the expression of CTGF and collagens I and IV in human aortic endothelial cells and mesangial cells are induced by low density lipoproteins (LDL). This LDL-induced increase in CTGF and collagens was mediated via autocrine activation of TGF-P and members of the MARK pathway. In addition, stimulation of the MARK pathway by LDL is mediated via activation of sphingosine kinase. We hypothesize that in diabetes, increased levels of abnormal or modified lipoproteins leads to the induction of CTGF, which in turn plays a pivotal role in the initiation and progression of diabetic vascular complications. Our specific aims are:1) Define the role and contribution of CTGF to the initiation and progression of vascular and renal disease in the DCCT/EDIC cohort of type 1 diabetic patients. We hypothesize that increases in the levels of CTGF leads to the development of diabetic vascular and renal disease. This will be demonstrated by determining whether type 1 diabetic patients who develop renal and vascular disease have prior increases in the levels of CTGF compared with type 1 diabetic patients who do not develop renal and vascular disease. 2) Elucidating the mechanisms through which lipoproteins modulate the production of biomarkers of vascular complications. We hypothesize that the cellular actions of lipoproteins to promote sclerosis of vascular and renal cells are mediated via increased expression of CTGF. The proposed studies bridge both clinical and basic research aimed at defining the risk factors and mechanisms of macrovascular disease in diabetes.

尚未完全定义有助于糖尿病中血管疾病发展的危险因素。这 该建议的总体目的是阐明脂蛋白之间的细胞和分子相互作用 和结缔组织生长因子（CTGF）及其对血管疾病发展的贡献 在1型糖尿病中，并阐明了此过程中涉及的基本机制。我们的发现类型 1名糖尿病患者，首次证明，CTGF与血管疾病风险之间的关联 诸如高血压，微量白蛋白尿和脂质升高之类的因素。此外，我们确定了一本小说 CTGF基因的启动子区域的多态性与蛋白尿相关联。这 多态性患者患有微量白蛋白尿的相对风险是患者的3倍 没有多态性。在细胞级别，我们的数据表明CTGF和 人主动脉内皮细胞中的胶原I和IV由低密度诱导 脂蛋白（LDL）。 LDL诱导的CTGF和胶原蛋白的增加是通过自分泌激活介导的 TGF-P和Mark途径的成员。另外，LDL对Mark途径的刺激为 通过激活鞘氨醇激酶介导。我们假设在糖尿病中，异常水平增加 或修饰的脂蛋白导致CTGF的诱导，而CTGF又在开始中起着关键作用 糖尿病血管并发症的进展。我们的具体目的是：1）定义 DCCT/EDIC 1型血管和肾脏疾病的引发和进展的CTGF 糖尿病患者。我们假设CTGF水平的增加导致糖尿病的发展 血管和肾脏疾病。这将通过确定1型糖尿病患者是否 与1型糖尿病相比 不发展肾脏和血管疾病的患者。 2）阐明通过 脂蛋白调节血管并发症的生物标志物的产生。我们假设 脂蛋白促进血管和肾细胞硬化症的细胞作用是通过增加 CTGF的表达。拟议的研究桥接临床和基础研究旨在定义风险 糖尿病中大血管疾病的因素和机制。