LIPOPROTEINS, CTGF AND DIABETIC VASCULAR & RENAL DISEASE

导致糖尿病血管疾病发展的危险因素尚未完全确定。的 该提案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。我们的发现在类型 1例糖尿病患者，首次证明CTGF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。另外，我们发现了一本小说 CTGF基因启动子区的多态性与白蛋白尿增加有关。的 携带该多态性的患者发生微量白蛋白尿的相对风险比携带该多态性的患者高3倍。 没有多态性。在细胞水平上，我们的数据表明CTGF的表达和 人主动脉内皮细胞和肾小球系膜细胞中的胶原I和IV被低密度诱导 脂蛋白（LDL）。这种LDL诱导的CTGF和胶原增加是通过自分泌激活介导的 TGF-β和MARK通路的成员。此外，LDL对MARK通路的刺激是 通过激活鞘氨醇激酶介导。我们假设在糖尿病中， 或修饰的脂蛋白导致CTGF的诱导，CTGF反过来在启动和 糖尿病血管并发症的进展。我们的具体目标是：（1）确定 CTGF与1型DCCT/EDIC队列中血管和肾脏疾病的发生和进展 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型糖尿病患者相比，患有肾脏和血管疾病的患者CTGF水平先前增加 未发生肾脏和血管疾病的患者。2)阐明通过哪些机制 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。拟议的研究将临床研究和旨在确定风险的基础研究联系起来 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.