EICOSANOIDS, ANGIOGENESIS, AND RETINOPATHY

描述（由申请人提供）：组织损伤后的炎症被认为是各种疾病的发生和发展的重要因素，包括视网膜病变、癌症和动脉粥样硬化。磷脂酶A2s （PLA2s）是一组分解磷脂生成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。越来越多的证据表明，PLA2、花生四烯酸及其类二十烷代谢产物在调节细胞迁移、增殖和凋亡中发挥作用。此外，最近使用非甾体类抗炎药的研究揭示了类二十烷在血管生成中的潜在作用。基于这些知识，我们假设类二十烷，特别是花生四烯酸的脂氧合酶/单氧合酶代谢物，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中发挥重要作用。为了测试类二十烷酸在血管生成中的作用，我们将解决以下4个具体目标：1)鉴定视网膜内皮细胞产生的类二十烷酸，并通过体外和体内模型确定其对血管生成的影响。2)研究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PI3K/Akt通路在血管生成类二十烷细胞诱导的EC迁移和增殖中的作用。4)鉴定类二十烷酸诱导血管生成的效应分子，研究其在内皮细胞和视网膜色素上皮细胞中的表达调控机制。这一建议的结果将为鉴定特定的血管生成类二十烷提供新的信息，并阐明这些脂质分子刺激血管生成的潜在机制。反过来，这些知识可以用于开发预防诸如增殖性视网膜病变等疾病进展的治疗方法。

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. 1 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 4 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.