Role of Cyclooxygenase stimulated Neovascularization in Diabetic Nephropathy

描述(由申请人提供)： 在美国，糖尿病肾病是终末期肾病的主要单一原因。糖尿病肾病与血管疾病有关，包括视网膜病变、伤口愈合障碍和神经病变。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的增加。然而，目前尚不清楚是哪条分子途径/S调控糖尿病肾小球血管生成。环氧合酶(COX)1和2是前列腺素E2(PGE2)生成的关键酶。值得注意的是，COX-2在糖尿病小鼠的肾皮质和髓质中都过度表达。观察到，用COX-2抑制剂治疗糖尿病小鼠减少了促血管生成分子的表达和蛋白尿，有力地表明了COX衍生的前列腺素在糖尿病肾病中的作用。由于1)COX在糖尿病肾脏中表达增加，2)PGE2刺激血管生成，3)PGE2增加内皮通透性，4)PGE2 EP4受体在肾小球高表达，我们推测在糖尿病肾脏疾病中激活了一个功能性的前列腺素依赖途径，促进了肾小球血管生成。为了验证这一假设，我们将评估1)COX-1和COX-2衍生的前列腺素在I型糖尿病小鼠模型中对新生血管形成的作用；2)微粒体前列腺素E2合成酶在I型糖尿病中PGE2的产生和随后的肾小球新生血管中的作用；3)肾小球内皮和足细胞EP4在糖尿病进展中的作用。本研究将使我们不仅能够明确COXS、PGE2及其受体在1型糖尿病中如何改变肾小球微血管生成，而且能够确定阻止PGE2合成和/或EP受体激活是否可能为治疗糖尿病肾病血管生成异常提供一种特异的治疗策略。 这项工作将是布雷耶博士和波齐博士的共同努力。15年来，布雷耶博士的团队一直在研究肾脏环氧合酶和PGE2的作用，并培育了几个用于研究前列腺素功能的转基因小鼠模型。他的团队还拥有丰富的糖尿病肾病小鼠模型表型鉴定经验。Pozzi博士研究了整合素(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动态平衡中的作用，这两个方面与糖尿病肾病相关。最近，她研究了COX-2衍生的前列腺素E_2及其受体EP4在肿瘤血管生成控制中的作用。此外，Pozzi博士和Breyer博士在JBC上发表了一篇关于COX-2在肾髓质间质细胞存活中的作用的文章。我们认为，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，并利用了他们对细胞分化和生存中的前列腺素途径的共同兴趣

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