ROLE OF ANGPTL4, AN ANGIOGENIC MEDIATOR, IN ARTHRITIS

血管生成介质 ANGPTL4 在关节炎中的作用

• 批准号: 7650338
• 负责人: SHERRY L THORNTON
• 金额: $ 8.78万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650338
• 关键词: Adipose tissue; Angiogenesis Inhibition; Angiogenesis Inhibitors; Angiopoietin-1; Angiopoietins; Animal Model; Apoptosis; Arthritis; Binding; Biochemical; Blood Vessels; Cell Line; Cell surface; Cells; Clinical; Collagen Arthritis; Data; Databases; Disease; Drug or chemical Tissue Distribution; Endothelial Cells; Event; Gene Expression; Genes; Human; In Vitro; Infiltration; Inflammation Mediators; Inflammatory; Kidney; Liver; Mediating; Mediator of activation protein; Messenger RNA; Mus; Onset of illness; Pathogenesis; Play; Process; Protein Family; Reagent; Recombinants; Rheumatoid Arthritis; Role; Score; Severities; Synovial Fluid; Synovial Membrane; Testing; Time; Tissues; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; angiogenesis; crosslink; cytokine; human angiopoietin-like 4 protein; mouse model; neutralizing antibody; novel therapeutics; protein aminoacid sequence; receptor

Angiogenesis is likely to play a key role in the pathogenesis of inflammatory arthritis. Several angiogenic molecules, including vascular endothelial growth factor and angiopoietin 1, are increased during rheumatoid arthritis (RA), and inhibition of angiogenesis suppresses arthritis in animal models, such as collagen-induced arthritis (CIA). We recently identified a pro-angiogenic gene, angiopoietin-like 4 (Angptl4), as the seventh most highly over-expressed mRNA in arthritic paws of mice with CIA. Expression of human Angptl4 mRNA was also substantially increased in human arthritic synovium. Angiopoietin-like 4 (Angptl4) is structurally and functionally similar to the angiopoietins, in that it specifically inhibits apoptosis of vascular endothelial cells. Expression of Angptl4 as assessed in mice and humans is limited primarily to liver, kidney, adipose tissue and inflamed synovium. This limited tissue distribution suggests that Angptl4 may play a distinct angiogenic role in arthritic tissue. Specific targeting of angiogenic events occurring within arthritic synovium may be favorable therapeutically. Angptl4 binds endothelial cells and can induce tubule formation of endothelial cells in vitro. Since Angptl4 binds to and exerts specific effects on endothelial cells, it is highly likely that a receptor for Angptl4 on endothelial cells mediates these effects. Therefore, Angptl4 and its putative receptor represent a major, targetable axis in the treatment of inflammatory arthritis. In this proposal we will develop the key reagents needed to test the hypothesis that Angptl4 increases inflammatory processes by promoting angiogenesis in arthritic synovial tissues. We directly test this hypothesis by (1) determining the effects of Angptl4 depletion on arthritis in the CIA mouse model and by (2) identifying and characterizing the receptor(s) for Angptl4 on endothelial cells.

血管生成可能在炎症性关节炎的发病机制中发挥关键作用。几种血管生成 分子，包括血管内皮生长因子和血管生成素 1，在类风湿期间增加 关节炎 (RA)，抑制血管生成可抑制动物模型中的关节炎，例如胶原诱导的关节炎 关节炎（CIA）。我们最近发现了一种促血管生成基因，血管生成素样 4 (Angptl4)，作为第七个基因。 患有 CIA 的小鼠关节炎爪子中 mRNA 过度表达最高。人Angptl4 mRNA的表达 在人类关节炎滑膜中也显着增加。血管生成素样 4 (Angptl4) 在结构上和 功能上与血管生成素相似，它特异性抑制血管内皮细胞的凋亡。 在小鼠和人类中评估的 Angptl4 表达主要限于肝脏、肾脏、脂肪组织 和发炎的滑膜。这种有限的组织分布表明 Angptl4 可能发挥独特的血管生成作用 在关节炎组织中的作用。关节炎滑膜内发生的血管生成事件的特异性靶向可能是 有利于治疗。 Angptl4结合内皮细胞并能诱导内皮细胞的小管形成 体外。由于 Angptl4 与内皮细胞结合并对内皮细胞发挥特定作用，因此很可能 内皮细胞上的 Angptl4 受体介导这些作用。因此，Angptl4 及其推定受体 代表了治疗炎症性关节炎的一个主要的、可靶向的轴。在本提案中，我们将开发 检验 Angptl4 通过以下方式增加炎症过程这一假设所需的关键试剂 促进关节炎滑膜组织中的血管生成。我们通过 (1) 确定 Angptl4 耗竭对 CIA 小鼠模型中关节炎的影响，并通过 (2) 识别和表征 内皮细胞上的 Angptl4 受体。