EICOSANOIDS, ANGIOGENESIS, AND RETINOPATHY

类花生酸、血管生成和视网膜病变

基本信息

批准号：
7433842
负责人：
GADIPARTHI N RAO
金额：
$ 34.73万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7433842
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Acids Address Affect Apoptosis Arachidonic Acids Atherosclerosis Biological Biological Assay Cell Hypoxia Condition Data Dermal Development Disease Disease Progression Dominant-Negative Mutation Dose Eicosanoid Production Eicosanoids Endothelial Cells Enzymes Epithelial Cells Event Family Fibroblast Growth Factor 2 G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Genes Growth Growth Factor Guanosine Triphosphate Phosphohydrolases Human Hypoxia In Vitro Inflammation Inflammatory Injury Investigation Knowledge Lipids Lipoxygenase Lysophospholipids Malignant Neoplasms Measures Mediating Metabolism Mixed Function Oxygenases Molecular Non-Steroidal Anti-Inflammatory Agents Oxidants Oxidative Stress PDPK1 gene Pathogenesis Pathway interactions Phospholipase Phospholipase A2 Phospholipids Phosphotransferases Play Prevention Principal Investigator Production Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Kinase C Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Regulation Reporting Retinal Retinal Diseases Role STAT protein Stress Testing Therapeutic Time Study Tissues Transcription Factor AP-1 Tube Vascular Endothelial Growth Factors Work angiogenesis base cell motility chorioallantoic membrane cyclooxygenase 1 cyclooxygenase 2 human FRAP1 protein in vivo Model neutralizing antibody novel programs response retinal angiogenesis rho

项目摘要

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.

描述（由申请人提供）：组织损伤后的炎症被认为对于包括视网膜病、癌症和动脉粥样硬化在内的各种疾病的发生和进展很重要。磷脂酶 A2 (PLA2) 是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。增殖性视网膜病进展的主要事件之一是血管生成。内皮细胞（EC）迁移和增殖是血管生成的关键事件。新的证据表明 PLA2、花生四烯酸及其类二十烷酸代谢物在细胞迁移、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二十烷酸在血管生成中的潜在作用。基于这些知识，我们假设类二十烷酸，特别是花生四烯酸的脂加氧酶/单加氧酶代谢物，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，我们将解决以下四个具体目标：1）鉴定视网膜内皮细胞中产生的类二十烷酸，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) 测试Jak/STAT和PI3K/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) 鉴定类二十烷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调节的机制。该提案的结果将为鉴定特定的血管生成类二十烷酸和阐明这些脂质分子刺激血管生成的潜在机制提供新的信息。这些知识反过来可用于开发预防增殖性视网膜病等疾病进展的疗法。