Non-COX Arachidonic Acid Metabolites and Angiogenesis

非 COX 花生四烯酸代谢物和血管生成

基本信息

批准号：
7192456
负责人：
GADIPARTHI N RAO
金额：
$ 34.61万
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：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7192456
关键词：
1-Phosphatidylinositol 3-Kinase 70-kDa Ribosomal Protein S6 Kinases Abbreviations Acids Address Affect Apoptosis Arachidonic Acids Atherosclerosis Biological Blood Vessels Development Diabetic Retinopathy Dinoprost Disease Disease Progression Dominant-Negative Mutation Dose Eicosanoid Production Eicosanoids Endothelial Cells Enzymes Event Family Fibroblast Growth Factor 2 G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Genes Growth Guanosine Triphosphate Phosphohydrolases Human IL8 gene In Vitro Inflammation Injury Interleukin-8 Investigation Knowledge Lipids Lipoxygenase Lysophospholipids Malignant Neoplasms Metabolism Mixed Function Oxygenases Molecular Non-Steroidal Anti-Inflammatory Agents Oxidants Oxidative Stress PDPK1 gene Pathogenesis Pathway interactions Phospholipase Phospholipase A2 Phospholipids Phosphotransferases Platelet Activating Factor Play Prevention Principal Investigator Process Production Prostaglandin-Endoperoxide Synthase Protein Kinase C RNA Interference Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Regulation Reporting Retinal Diseases Role STAT protein Smooth Muscle Myocytes Stress Testing Therapeutic Time Study Tissues Transcription Factor AP-1 Vascular Endothelial Cell Vascular Endothelial Growth Factors Work angiogenesis base cell motility chromatin immunoprecipitation cyclooxygenase 1 cyclooxygenase 2 doxorubicin/fluorouracil/melphalan protocol human FRAP1 protein in vivo Model inhibitor/antagonist neovascularization neutralizing antibody novel novel strategies programs promoter response rho

项目摘要

Inflammation that follows tissue injury is believed to be important in the initiation and progression of various diseases including, atherosclerosis, cancer, and retinopathy. Phospholipase A2s (PLA2s), a group of enzymes that breakdown phospholipids generating arachidonic acid and lysophospholipids have been implicated in inflammation. One of the major events underlying the progression of atherosclerosis 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 influence the pathogenesis of atherosclerosis. To test the role of eicosanoids in angiogenesis we will address the following four specific aims: 1. To identify eicosanoids produced in human microvascular endothelial cells (HMVEC) and determine their effects on angiogenesis using in vitro and in vivo models. 2. To determine the effects of angiogenic eicosanoids on HMVEC migration and proliferation. 3. To test the role of the Jak/STAT and PI3K/Akt pathways in angiogenic eicosanoid-induced HMVEC migration and proliferation. 4. To identify the effector molecules of eicosanoid-induced angiogenesis and study the mechanisms underlying their regulation of expression in HMVEC and vascular smooth muscle 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 atherosclerosis.

据信组织损伤后的炎症在各种疾病的开始和进展中很重要，包括动脉粥样硬化，癌症和视网膜病变。磷脂酶A2S（PLA2S），这是一组酶，这些酶对产生花生四烯酸和溶物磷脂的磷脂已经与炎症有关。动脉粥样硬化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中的关键事件。新兴的证据表明，PLA2，花生四烯酸及其类黄花酸代谢产物在调节细胞迁移，增殖和凋亡中起作用。此外，使用非甾体类抗炎药的最新研究揭示了eicosanoids在血管生成中的潜在作用。基于这一知识，我们假设类花生酸，尤其是花生四烯酸的脂氧合酶 - 单氧酶代谢物，在血管生成中起着重要作用，从而影响动脉粥样硬化的发病机理。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特定目的：1。鉴定在人类微血管内皮细胞（HMVEC）中产生的类花生酸酯（HMVEC），并确定其使用体外和体内模型对血管生成的影响。 2。确定血管生成类花生酸对HMVEC迁移和增殖的影响。 3。测试JAK/STAT和PI3K/AKT途径在血管生成类花生酸诱导的HMVEC迁移和增殖中的作用。 4。确定eicosanoid诱导的血管生成的效应分子，研究其在HMVEC和血管平滑肌细胞中表达调节的机制。该提案的结果将提供有关鉴定特定血管生成类花生酸的新信息，以及阐明这些脂质分子刺激血管生成的基本机制。反过来，这种知识对于开发治疗剂在预防诸如动脉粥样硬化等疾病的进展方面可能很有用。