LIPOPROTEINS, CTGF AND DIABETIC VASCULAR & RENAL DISEASE

导致糖尿病血管疾病发展的危险因素还没有完全确定。这个 这项建议的总体目标是阐明脂蛋白之间的细胞和分子相互作用 结缔组织生长因子(CTGF)及其在血管疾病发展中的作用 在1型糖尿病中，并阐明参与这一过程的潜在机制。我们在类型上的发现 1名糖尿病患者首次证明了结缔组织生长因子与血管疾病风险之间的关联 高血压、微量白蛋白尿和血脂升高等因素。此外，我们还确定了一部小说 CTGF基因启动子区域的多态性与蛋白尿增加相关。这个 基因多态患者发生微量白蛋白尿的相对风险是患者的3倍 没有这种多态。在细胞水平上，我们的数据表明CTGF和 低密度诱导人主动脉内皮细胞和系膜细胞的I型和IV型胶原 脂蛋白(LDL)。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介导的 转化生长因子-β和MARK途径的成员。此外，低密度脂蛋白对MARK通路的刺激作用 通过激活鞘氨醇激活酶进行调节。我们假设在糖尿病患者中，异常水平增加 或修饰的脂蛋白导致CTGF的诱导，而CTGF又在启动和 糖尿病血管并发症的进展。我们的具体目标是：1)确定 CTGF在1型DCCT/EDIC队列中血管和肾脏疾病的发生和发展中的作用 糖尿病患者。我们假设CTGF水平的升高导致糖尿病的发生 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，发生肾脏和血管病变的患者CTGF水平先期升高 不发生肾脏和血管疾病的患者。2)阐明了通过什么机制 脂蛋白调节血管并发症生物标志物的产生。我们假设 脂蛋白促进血管和肾细胞硬化的细胞作用是通过增加 CTGF的表达。拟议的研究连接了旨在确定风险的临床研究和基础研究。 糖尿病大血管病变的因素和机制。

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.