The Role of Angiopoietin-1 in Rheumatoid Arthritis

血管生成素-1 在类风湿关节炎中的作用

• 批准号: 6544885
• 负责人: J Peter PETER OETTGEN
• 金额: $ 27.97万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6544885
• 关键词: angiogenesis; angiopoietins; clinical research; fibroblasts; flow cytometry; human subject; immunocytochemistry; in situ hybridization; inflammation; laboratory mouse; patient oriented research; rheumatoid arthritis; synovial membrane; transcription factor; transfection; vascular endothelium

DESCRIPTION (provided by applicant): Angiogenesis is a critical component of the inflammation associated with rheumatoid arthritis (RA). The longterm goals of the proposed studies are to understand the molecular mechanisms underlying angiogenesis in RA and thereby identify novel therapeutic approaches to treating inflammatory arthritis. Angiogenesis is a complex, multistep process that eventually leads to the development of mature blood vessels. Several angiogenic growth factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been identified within the rheumatoid synovium, all of which promote the early steps of angiogenesis. Recently, a novel angiogenic factor, Angiopoietin-1(Ang-1) was identified, that has the unique properties of facilitating the later stages of angiogenesis. We have determined that Ang-1 is expressed in synovial fibroblasts derived from patients with RA. Furthermore, proinflammatory cytokines can markedly upregulate the expression of Ang-1 in these cells and induce Ang-1 in other cell types found in the rheumatoid synovium including monocytes and chondrocytes. In addition to its role in promoting vessel maturation Ang-1 is a potent chemoattractant. The strong expression of Ang-1 in synovial fibroblasts may facilitate the migration of endothelial cells to the growing pannus. The molecular mechanisms by which Ang-1 mediates its effects in endothelial cells are poorly understood. We have also determined that the Ets factor NERF2 is induced by Ang- 1 in endothelial cells suggesting that NERF2 is a transcriptional regulator of Ang-1 mediated effects. The hypothesis for this proposal is that Ang-1 is one of the critical factors required for the angiogenic response in rheumatoid arthritis. The goals of this grant application are to define the biological role of Ang- 1 in promoting the angiogenic component of inflammatory arthritis, to further define the biological role of NERF2 as a transcriptional mediator of Ang- 1, and examine the therapeutic potential of blocking Ang- 1 during the development of inflammatory arthritis. Thus the Specific Aims are to determine: 1. What is the biological role of Ang-1 in inflammatory arthritis? 2. What is the role of the Ets transcription factor NERF2, in mediating the biological effects of Ang-1? 3. What is the therapeutic effect of blocking the function of Ang-1 in inflammatory arthritis? The approaches that will be used to address these questions include immunohistochemistry, in situ hybridization, the examination of synovial tissue samples from patients with RA and animals with collagen induced arthritis, adenoviral and retroviral gene delivery methods, assays of endothelial function, and flow cytometry.

描述（由申请人提供）：血管生成是类风湿性关节炎（RA）相关炎症的关键组成部分。拟议研究的长期目标是了解RA血管生成的分子机制，从而确定治疗炎症性关节炎的新治疗方法。血管生成是一个复杂的、多步骤的过程，最终导致成熟血管的发育。包括血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）在内的几种血管生成生长因子已经在类风湿滑膜中被发现，它们都促进了血管生成的早期步骤。最近，一种新的血管生成因子ang1 （angiooietin -1）被发现，它具有促进晚期血管生成的独特特性。我们已经确定Ang-1在RA患者的滑膜成纤维细胞中表达。此外，促炎细胞因子可以显著上调这些细胞中Ang-1的表达，并诱导类风湿滑膜中其他类型细胞（包括单核细胞和软骨细胞）表达Ang-1。除了在促进血管成熟方面的作用外，Ang-1还是一种有效的化学引诱剂。滑膜成纤维细胞中Ang-1的强烈表达可能促进内皮细胞向生长的滑膜迁移。ang1介导内皮细胞作用的分子机制尚不清楚。我们还确定内皮细胞中的Ets因子NERF2是由Ang-1诱导的，这表明NERF2是Ang-1介导作用的转录调节因子。这一提议的假设是，ang1是类风湿性关节炎血管生成反应所需的关键因素之一。本资助申请的目标是确定Ang- 1在促进炎症性关节炎血管生成成分中的生物学作用，进一步确定NERF2作为Ang- 1转录介质的生物学作用，并检查在炎症性关节炎发展过程中阻断Ang- 1的治疗潜力。因此，具体目标是确定：1。ang1在炎症性关节炎中的生物学作用是什么？2. Ets转录因子NERF2在介导ang1生物学效应中的作用是什么？3. 阻断ang1功能对炎性关节炎的治疗效果如何？将用于解决这些问题的方法包括免疫组织化学、原位杂交、检查RA患者和胶原诱导关节炎动物的滑膜组织样本、腺病毒和逆转录病毒基因传递方法、内皮功能测定和流式细胞术。