OKHSC COBRE: OXIDATIVE STRESS AND INFLAMMATION IN DIABETIC RETINOPATHY

OKHSC COBRE：糖尿病视网膜病变中的氧化应激和炎症

• 批准号: 8167972
• 负责人: XIN ZHANG
• 金额: $ 21.48万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167972
• 关键词: Angiogenesis Inhibitors; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Blindness; Blood Vessels; Blood-Retinal Barrier; Computer Retrieval of Information on Scientific Projects Database; Development; Diabetes Mellitus; Diabetic Retinopathy; Endothelial Cells; Enzymes; Extravasation; Functional disorder; Funding; Generations; Grant; Inflammation; Inflammatory; Institution; Mitochondria; Mus; NADPH Oxidase; Nerve Degeneration; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathologic; Pericytes; Peroxonitrite; Play; Production; Research; Research Personnel; Resources; Retina; Retinal; Retinal Neovascularization; Role; Signal Pathway; Source; Superoxides; Tight Junctions; Transgenic Mice; United States National Institutes of Health; Up-Regulation; Xanthine Oxidase; base; diabetic; normal aging; novel; oxidation; pigment epithelium-derived factor; retinal neuron; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetic retinopathy (DR) is a leading cause of blindness in the US. The early pathologic hallmarks of DR nclude retinal vascular cellular dysfunction, blood-retinal barrier (BRB) breakdown, vascular leakage and neural degeneration. Although the mechanisms largely unknown, recent studies suggest that oxidative stress and inflammation plays a critical role in the pathogenesis of DR. Pigment epithelium-derived factor (PEDF) is an endogenous angiogenic inhibitor. Accumulating evidence suggests beneficial effects of PEDF in DR, i.e. nhibition of retinal neovascularization and reduction of vascular leakage; however, the mechanisms are not fully elucidated. Our recent novel studies demonstrated that PEDF is a potent anti-inflammatory factor and inhibits vascular leakage in DR. Moreover, PEDF reduces diabetes-induced superoxide (O2.-) and peroxynitrite (ONOO-) production in retinal pericytes and in diabetic retina. Based on these important findings, we hypothesize that PEDF ameliorates diabetic retinal complications by reducing oxidative stress and inflammation. In Aim 1, we will focus on establishing the activity of PEDF as an endogenous anti-oxidant factor by determining the effects of PEDF on O2.-/ONOO- generation, pro-inflammatory factor expression, endothelial tight junction and neuron degeneration in cultured retinal endothelial cells and retinal neurons. We will also determine if over-expressing or down-regulating PEDF in the retina will ameliorate or augment oxidative stress and inflammation in DR by comparing these parameters in diabetic and normal age-matched PEDF transgenic mice, PEDF deficient mice and wildtype mice. In Aim 2, we will explore the mechanisms by which PEDF inhibits O2.-/ONOO- formation. We hypothesize that PEDF suppresses diabetes-induced O2.- generation via up-regulation of anti-oxidant enzymes and / or protection of mitochondrial function. If our hypothesis is proved, we will pursue the signaling pathway to explore how PEDF regulates anti-oxidant enzymes and / or how PEDF protects mitochondrial function. If the results indicate that other mechanisms may also contribute to the PEDF effects on anti-oxidation, we will determine alternatively if and how PEDF reduces superoxide generation by inhibiting the major redox enzymes, i.e. NADPH oxidase, xanthine oxidase and eNOS. The success of this project will not only identify a novel pathogenic mechanism for DR, but also contribute to the development of new therapies using endogenous angiogenic inhibitors.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 糖尿病性视网膜病（DR）是美国失明的主要原因。 Nclude视网膜血管细胞功能障碍，血液 - 视网膜屏障（BRB）崩溃，血管泄漏和神经变性的早期病理标志。尽管这些机制在很大程度上未知，但最近的研究表明，氧化应激和炎症在DR的发病机理中起关键作用。色素上皮衍生因子（PEDF）为 内源性血管生成抑制剂。积累的证据表明，PEDF在DR中的有益影响，即视网膜新生血管形成和减少血管渗漏的作用；但是，这些机制尚未完全阐明。我们最近的新研究表明，PEDF是有效的抗炎因子， 抑制DR中的血管泄漏。此外，PEDF减少了视网膜周细胞和糖尿病性视网膜中糖尿病诱导的超氧化物（O2.-）和过氧亚硝酸盐（Onoo-）的产生。基于这些重要发现，我们假设PEDF通过减少氧化应激来改善糖尿病性视网膜并发症 和炎症。在AIM 1中，我们将专注于通过确定PEDF对O2的影响。-/onoo-onoo产生，促炎性因子的表达，内皮紧密连接和神经元变性对培养的视网膜内皮细胞和视网膜神经元的影响，通过确定PEDF对O2的影响来确定作为内源性抗氧化因子的活性。我们还将确定视网膜中过度表达或下调的PEDF是否会改善或增加 通过比较糖尿病和正常年龄匹配的PEDF转基因小鼠，PEDF缺乏小鼠和野生型小鼠中的这些参数，在DR中的氧化应激和炎症。在AIM 2中，我们将探索PEDF抑制O2 .-/onoo-onoo-ono-onoo形成的机制。我们假设PEDF抑制了糖尿病诱导的O2。-通过上调抗氧化酶和 /或线粒体功能的保护。如果我们 证明了假设，我们将追求信号通路，以探索PEDF如何调节抗氧化酶和 /或PEDF如何保护线粒体功能。如果结果表明其他机制也可能有助于PEDF对抗氧化作用，我们将确定是否以及如何使用PEDF 通过抑制主要的氧化还原酶，即NADPH氧化酶，黄嘌呤氧化酶和eNOS来减少超氧化物的产生。该项目的成功不仅将确定DR的新型致病机制，而且还可以使用内源性血管生成抑制剂开发新疗法。