EICOSANOIDS, ANGIOGENESIS, AND RETINOPATHY

描述（由申请人提供）：组织损伤后的炎症被认为在包括视网膜病、癌症和动脉粥样硬化在内的各种疾病的起始和进展中是重要的。磷脂酶A2（PLA 2），一组分解磷脂产生花生四烯酸和溶血磷脂的酶，与炎症有关。增殖性视网膜病变进展的主要事件之一是血管生成。内皮细胞（EC）的迁移和增殖是血管生成的关键事件。新出现的证据表明，PLA 2，花生四烯酸及其类花生酸代谢产物在细胞迁移，增殖和凋亡的调节中发挥作用。此外，最近使用非甾体抗炎药的研究揭示了类花生酸在血管生成中的潜在作用。基于这些知识，我们假设类花生酸，特别是花生四烯酸的脂氧合酶/单加氧酶代谢产物，在血管生成中发挥重要作用，从而在视网膜病变的发病机制。为了测试类花生酸在血管生成中的作用，我们将解决以下四个具体目标：1）鉴定视网膜内皮细胞中产生的类花生酸，并使用体外和体内模型确定它们对血管生成的影响。2)确定血管生成类二十烷酸对EC迁移和增殖的影响。3)检测Jak/STAT和PI 3 K/Akt通路在血管生成类二十烷酸诱导的EC迁移和增殖中的作用。4)鉴定类花生酸诱导血管生成的效应分子，并研究其在EC和视网膜色素上皮细胞中表达的调控机制。这一建议的结果将提供新的信息识别特定的血管生成类花生酸和阐明这些脂质分子刺激血管生成的潜在机制。这些知识，反过来，可能是有用的，在开发治疗方法，在预防疾病的进展，如增殖性视网膜病变。

DESCRIPTION (provided by applicant): Inflammation that follows tissue injury is believed to be important in the initiation and progression of various diseases including retinopathy, cancer and atherosclerosis. Phospholipase A2s (PLA2s), a group of enzymes that break down phospholipids generating arachidonic acid and lysophospholipids have been implicated in inflammation. One of the major events underlying the progression of proliferative retinopathy is angiogenesis. Endothelial cell (EC) migration and proliferation are critical events in angiogenesis. Emerging evidence suggests that PLA2, arachidonic acid and its eicosanoid metabolites play a role in the regulation of cell migration, proliferation, and apoptosis. In addition, recent investigations using nonsteroidal anti- inflammatory drugs reveal a potential role for eicosanoids in angiogenesis. Based on this knowledge, we hypothesize that eicosanoids, particularly the lipoxygenase/monooxygenase metabolites of arachidonic acid, play an important role in angiogenesis and thereby in the pathogenesis of retinopathy. To test the role of eicosanoids in angiogenesis we will address the following four specific aims: 1) To identify eicosanoids produced in retinal endothelial cells and determine their effects on angiogenesis using in vitro and in vivo models. 2) To determine the effects of angiogenic eicosanoids on EC migration and proliferation. 3) To test the role of the Jak/STAT and PI3K/Akt pathways in angiogenic eicosanoid-induced EC migration and proliferation. 4) To identify the effector molecules of eicosanoid-induced angiogenesis and study the mechanisms underlying their regulation of expression in EC and retinal pigmentary epithelial cells. The results of this proposal will provide novel information on the identification of specific angiogenic eicosanoids and on elucidation of the underlying mechanisms by which these lipid molecules stimulate angiogenesis. Such knowledge, in turn, could be useful in developing therapeutics in the prevention of progression of diseases such as proliferative retinopathy.