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LIPOPROTEINS, CTGF AND DIABETIC VASCULAR & RENAL DISEASE

脂蛋白、CTGF 和糖尿病血管

基本信息

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
项目类别：
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

项目摘要

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.

导致糖尿病患者发生血管疾病的危险因素尚未完全确定。的