Cyclooxygenase Stimulated Neovascularization in Diabetic

环加氧酶刺激糖尿病的新血管形成

• 批准号: 7043948
• 负责人: Matthew Douglas Breyer
• 金额: $ 30.42万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7043948
• 关键词: albuminuria; angiogenesis; biological signal transduction; cardiovascular disorder risk; cell differentiation; cyclooxygenase inhibitors; diabetic nephropathy; disease /disorder model; genetically modified animals; histopathology; insulin dependent diabetes mellitus; laboratory mouse; medical complication; microsomes; pathologic process; podocyte; prostaglandin E; prostaglandin endoperoxide synthase; prostaglandin receptor; protein structure function; receptor expression; renal glomerulus; vascular endothelium

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.

描述（由申请人提供）： 糖尿病性肾病（DN）是美国末期肾脏疾病的主要原因。 DN与血管疾病有关，包括视网膜病变，伤口愈合受损和神经病。尽管较少认可，但在1型糖尿病中也观察到肾小球新生血管形成增加。但是，目前尚不清楚糖尿病中哪种分子途径/S控制肾小球血管生成。环氧酶（COX）1和2是参与前列腺素E2（PGE2）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表达。观察到，用COX-2抑制剂治疗糖尿病小鼠可以降低促血管生成分子的表达以及蛋白尿，这强烈暗示了COX衍生的前列腺素在DN中的作用。当i）在糖尿病肾脏中观察到COX表达的增加，ii）ii）PGE2刺激血管生成，iii）PGE2增加了内皮渗透性，iv）iv）PGE2 EP4受体在肾小球中高度表达，我们在糖尿病中促进了糖尿病和促进性促进性的gle虫，我们假设一种功能性的Prostaglane Pathway是激活的。为了检验这一假设，我们将评估1）COX-1与Cox-2衍生的前列腺素对I型糖尿病小鼠模型中新生血管形成进展的贡献； 2）微粒体前列腺素E2合酶在PGE2产生中的作用以及I型糖尿病中的肾小球新生血管形成和3）3）肾小球内皮细胞EP4在糖尿病进展中的作用。这项研究不仅可以定义COX，PGE2及其受体如何改变1型糖尿病的肾小球微血管血管生成，而且还可以定义PGE2合成和/或EP受体激活是否可以为DN中改变的血管生成的治疗提供特定的治疗策略。 这项工作将是Drs之间的共同努力。 Breyer和Pozzi。 Breyer博士的小组一直在研究15年以上的肾脏环氧合酶和PGE2的作用，并生成了用于研究前列腺素功能的几种转基因小鼠模型。他的小组还具有糖尿病肾病的小鼠模型表型的丰富经验。 Pozzi博士研究整联蛋白的作用（1（1，是主要的胶原结合受体，在控制内皮细胞生物学和胶原蛋白稳态中的控制中，DN中的两个相关方面。最近，她研究了Cox-2衍生的PGE2的贡献，其受体EP4及其受体EP4在控制肿瘤生成的角色中，drs and pro ins in drs.pozzi。肾脏髓质细胞存活。我们认为，当前的建议在POZZI博士的血管生成方面的专业知识与Breyer博士在糖尿病肾病小鼠模型中的专业知识之间提供了协同作用，并借鉴了它们在细胞差异和生存方面的前烷途径中的共同兴趣。