ROLE OF ANGPTL4, AN ANGIOGENIC MEDIATOR, IN ARTHRITIS

血管生成介质 ANGPTL4 在关节炎中的作用

基本信息

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
项目类别：
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

项目摘要

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理中起关键作用。几种血管生成在类风湿病期间，包括血管内皮生长因子和血管生成素1的分子增加了关节炎（RA）和抑制血管生成可抑制动物模型中的关节炎，例如胶原蛋白诱导关节炎（CIA）。我们最近确定了一个促血管生成基因，即血管生成素样4（Angptl4）为第七与CIA的小鼠关节炎爪子中最高表达的mRNA。人类angptl4 mRNA的表达人类关节炎滑膜也大大增加了。血管生成素样4（Angptl4）在结构上是在功能上与血管生成素相似，因为它特别抑制了血管内皮细胞的凋亡。在小鼠和人类中评估的ANGPTL4的表达主要限于肝脏，肾脏，脂肪组织并发炎的滑膜。这种有限的组织分布表明Angptl4可能起独特的血管生成在关节组织中的作用。关节炎滑膜内发生的血管生成事件的特定靶向可能是在治疗上有利。 ANGPTL4结合内皮细胞，可以诱导内皮细胞的小管形成体外。由于ANGPTL4与内皮细胞结合并发挥特定影响，因此很有可能A 内皮细胞上ANGPTL4的受体介导了这些作用。因此，Angptl4及其推定的受体代表了炎症性关节炎治疗的主要靶向轴。在这个建议中，我们将发展测试ANGPTL4增加炎症过程的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，以及（2）识别和表征内皮细胞上的Angptl4受体。