LIPOPROTEINS, CTGF AND DIABETIC VASCULAR & RENAL DISEASE

描述(由申请人提供)：导致糖尿病血管疾病发展的危险因素尚未完全定义。这项建议的总体目标是阐明脂蛋白和结缔组织生长因子(CTGF)之间的细胞和分子相互作用及其在1型糖尿病血管疾病发展中的作用，并阐明这一过程中涉及的潜在机制。我们在1型糖尿病患者中的发现首次证明了CTGF与血管疾病风险因素之间的关联，如高血压、微量白蛋白尿和血脂升高。此外，我们在CTGF基因的启动子区域发现了一种与蛋白尿增加相关的新的多态。携带该基因多态的患者发生微量白蛋白尿的相对风险是未携带该基因的患者的3倍。在细胞水平上，我们的研究结果表明，人主动脉内皮细胞和系膜细胞中CTGF和I型、IV型胶原的表达是由低密度脂蛋白(LDL)诱导的。这种低密度脂蛋白诱导的CTGF和胶原蛋白的增加是通过自分泌激活转化生长因子-β和MARK通路的成员来调节的。此外，低密度脂蛋白对MARK通路的刺激是通过激活鞘氨醇激酶来实现的。我们假设，在糖尿病中，异常或修饰的脂蛋白水平的增加导致CTGF的诱导，而CTGF反过来在糖尿病血管并发症的发生和发展中发挥关键作用。我们的具体目标是：1)明确CTGF在1型糖尿病患者DCCT/EDIC队列中血管和肾脏疾病的发生和发展中的作用和贡献。我们假设CTGF水平的增加会导致糖尿病血管和肾脏疾病的发展。这一点将通过确定发生肾脏和血管疾病的1型糖尿病患者是否比没有发生肾脏和血管疾病的1型糖尿病患者更早地增加CTGF水平来证明。2)阐明脂蛋白调节血管并发症生物标志物产生的机制。我们推测，脂蛋白促进血管和肾细胞硬化的细胞作用是通过增加CTGF的表达来实现的。拟议的研究连接了临床和基础研究，旨在确定糖尿病大血管疾病的风险因素和机制。

DESCRIPTION (provided by applicant): 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.