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）： 糖尿病肾病（DN）是美国终末期肾病的主要单一原因。 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变。尽管认识较少，但在 1 型糖尿病中也观察到肾小球新生血管形成增加。然而，目前尚不清楚糖尿病中哪种分子途径控制肾小球血管生成。环加氧酶 (COX) 1 和 2 是参与前列腺素 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均过度表达。用 COX-2 抑制剂治疗糖尿病小鼠的观察结果减少了促血管生成分子的表达以及白蛋白尿，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 COX 表达增加，ii) PGE2 刺激血管生成，iii) PGE2 增加内皮通透性，以及 iv) PGE2 EP4 受体在肾小球中高表达，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) COX-1 与 COX-2 衍生的前列腺素类药物对 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 PGE2 产生和随后的肾小球新生血管形成中的作用，以及 3) 肾小球内皮细胞和足细胞 EP4 在糖尿病进展中的作用。这项研究不仅使我们能够确定 COX、PGE2 及其受体如何在 1 型糖尿病中改变肾小球微血管生成，而且还能确定阻止 PGE2 合成和/或 EP 受体激活是否可以为 DN 血管生成改变的治疗提供特定的治疗策略。 这项工作将是博士们的共同努力。布雷耶和波齐。 Breyer 博士的团队研究肾环氧合酶和 PGE2 的作用已超过 15 年，并建立了多种用于研究前列腺素功能的转基因小鼠模型。他的团队在糖尿病肾病小鼠模型的表型分析方面也拥有丰富的经验。 Pozzi 博士研究整合素（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稳态（DN 中的两个相关方面）中的作用。最近，她研究了 COX-2 衍生的 PGE2 及其受体 EP4 在控制肿瘤血管生成中的贡献。此外，Pozzi 和 Breyer 博士在 JBC 上发表了一篇关于 COX-2 在 DN 中的作用的文章。 肾髓质间质细胞的存活率。我们相信，本提案提供了 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存活中前列腺素途径的共同兴趣。