Role of Cyclooxygenase stimulated Neovascularization in Diabetic Nephropathy

描述（由申请人提供）： 糖尿病肾病（DN）是美国终末期肾病的主要单一原因。DN与血管疾病相关，包括视网膜病变、伤口愈合受损和神经病变。虽然认识较少，但在1型糖尿病中也观察到肾小球新生血管增加。然而，目前尚不清楚哪种分子途径控制糖尿病中的肾小球血管生成。环氧合酶（考克斯）1和2是参与前列腺素E2（PGE 2）生成的关键酶。值得注意的是，考克斯-2在糖尿病小鼠的肾皮质和髓质中过表达。观察到用考克斯-2抑制剂治疗糖尿病小鼠降低促血管生成分子的表达以及蛋白尿，强烈表明COX衍生的前列腺素类在DN中的作用。由于i）在糖尿病肾脏中观察到增加的考克斯表达，ii）PGE 2刺激血管生成，iii）PGE 2增加内皮通透性，和iv）PGE 2 EP 4受体在肾小球中高度表达，我们假设功能性前列腺素依赖性途径在糖尿病肾病中被激活并促进肾小球血管生成。为了检验这一假设，我们将评估1）考克斯-1与考克斯-2衍生的前列腺素类化合物对I型糖尿病小鼠模型中新血管形成进展的贡献; 2）微粒体前列腺素E2合酶在I型糖尿病中产生PGE 2和随后的肾小球新血管形成中的作用;和3）肾小球内皮细胞和足细胞EP 4在糖尿病进展中的作用。这项研究将使我们不仅能够确定COX，PGE 2及其受体如何改变1型糖尿病患者的肾小球微血管生成，而且还可以确定阻止PGE 2合成和/或EP受体激活是否可能为DN中改变的血管生成提供特定的治疗策略。 这项工作将是布雷耶博士和波齐博士的共同努力。Breyer博士的研究小组已经研究了肾脏环氧合酶和PGE 2的作用超过15年，并且已经产生了几种用于研究前列腺素功能的转基因小鼠模型。他的研究小组也有大量的经验表型小鼠模型的糖尿病肾病。Pozzi博士研究了整合素β 1（1，一种主要的胶原结合受体，在控制内皮细胞生物学和胶原稳态中的作用，这是DN的两个相关方面。最近，她研究了考克斯-2衍生的PGE 2及其受体EP 4在控制肿瘤血管生成中的作用。此外，Pozzi和Breyer博士在JBC上发表了一篇关于考克斯-2在肾髓质间质细胞存活中的作用的文章。我们相信目前的建议提供了Pozzi博士在血管生成方面的专业知识和Breyer博士在糖尿病肾病小鼠模型方面的专业知识之间的协同作用，并利用了他们在细胞分化和存活中的前列腺素途径方面的共同兴趣

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the major single cause of end stage renal disease in the United States. DN is associated with vascular disease, including retinopathy, impaired wound healing and neuropathy. Although less recognized, increased glomerular neovascularization has also been observed in type 1 diabetes. However, at present it is not clear which molecular pathway/s control glomerular angiogenesis in diabetes. Cyclooxygenases (COX) 1 and 2 are key enzymes involved in the generation of prostaglandin E2 (PGE2). Notably, COX-2 is over-expressed in both renal cortex and medulla of diabetic mice. The observation that treatment of diabetic mice with COX-2 inhibitors reduces the expression of pro-angiogenesis molecules as well as albuminuria, strongly suggest a role for COX-derived prostanoids in DN. As i) increased COX expression is observed in diabetic kidneys, ii) PGE2 stimulates angiogenesis, iii) PGE2 increases endothelial permeability, and iv) the PGE2 EP4 receptor is highly expressed in glomeruli, we hypothesize that a functional prostaglandin dependent pathway is activated in diabetic kidney disease and promotes glomerular angiogenesis. To test this hypothesis we will assess 1) the contribution of COX-1 versus COX-2 derived prostanoids to the progression of neovascularization in mouse models of type I diabetes; 2) the role of a microsomal prostaglandin E2 synthase in the production of PGE2 and consequent glomerular neovascularization in type I diabetes and 3) the role of the glomerular endothelial and podocytes EP4 in the progression of diabetic. This study will enable us not only to define how COXs, PGE2 and its receptors alter glomerular microvascular angiogenesis in the setting of type 1 diabetes, but also to define whether preventing PGE2 synthesis and/or EP receptor activation might provide a specific therapeutic strategy to the treatment for altered angiogenesis in DN. This work will be a joint effort between Drs. Breyer and Pozzi. Dr. Breyer's group has been studying the roles of renal cyclooxygenase and PGE2 for over 15 years and has generated several of the transgenic mouse models used to study prostanoid function. His group also has substantial experience phenotyping mouse models of diabetic nephropathy. Dr. Pozzi studies the role of integrin (1(1, a major collagen binding receptor, in the control of endothelial cell biology and collagen homeostasis, two relevant aspects in DN. Recently she has examined the contribution of COX-2-derived PGE2 and its receptor EP4 in the control of tumor angiogenesis. Moreover, Drs. Pozzi and Breyer published in JBC an article on the role of COX-2 in the renal medullary interstitial cell survival. We believe the present proposal provides synergy between Dr. Pozzi's expertise in angiogenesis and Dr. Breyer's expertise in mouse models of diabetic nephropathy, and draws on their common interest in the prostanoid pathway in cell differentiation and survival