Rac2 in integrin macrophage function

我们实验室的初步数据已经确定了Rac 2-/-小鼠中α v β 3和α 4 β 1整联蛋白介导的玻连蛋白巨噬细胞迁移的显著缺陷。α v β 3和α 4 β 1整联蛋白介导炎症的重要组分。 巨噬细胞必须使用α v整联蛋白迁移到炎症部位，在那里它们调节炎症和血管生成。此外，α v整联蛋白与基质降解酶、MMP和纤溶酶原激活系统非共价结合，以消化和重塑细胞外基质，这是伤口愈合、炎症和血管生成的必要组分。最近的证据表明α v β 3整联蛋白是自身免疫性关节炎的重要组分，阻断α v β 3的药物（功能阻断单克隆抗体，LM 609和/或RGD肽）可以改善关节炎状态。炎症和血管生成是自身免疫性关节炎发病机制的关键组成部分。我们在目的1中提出检查Rac 2对巨噬细胞和非造血细胞中α v β 3和α 4 β 1整联蛋白信号传导和迁移的影响，以努力检查血细胞中Rac 2信号传导的特异性。我们将研究血液特定的上游效应的整合素信号作为可能的组成部分的Rac 2依赖性整合素诱导的信号复合物在巨噬细胞。在目标2中，我们将在DBA/1小鼠中产生Rac 2缺陷型胶原诱导的关节炎模型，以评估Rac 2对通过控制炎症和血管生成介导的自身免疫的贡献。这些联合研究将有可能为开发用于治疗关节炎和其他自身免疫性疾病的抗炎药确定新的靶点。

Preliminary data from our laboratory has established a marked defect in alphavbeta3 and alpha4beta1 integrin directed migration of macrophages of vitronectin in the Rac2-/- mice. The alphavbeta3 and alpha4beta1 integrins mediate important components of inflammation. Macrophages must use the alphav integrins to migrate to sites of inflammation where they modulate inflammation and angiogenesis. Moreover the alphav integrins non-covalently associated with matrix degrading enzymes, MMPs and plasminogen activating systems to digest and remodel the extracellular matrix a necessary component of wound healing, inflammation and angiogenesis. Recent evidence has implicated the alphavbeta3 integrin as an important component of autoimmune arthritis and agents which block alphavbeta3 (function blocking monoclonal antibodies, LM609 and/or RGD peptides) can ameliorate the arthritic state. Both inflammation and angiogenesis are critical components of the pathogenesis of autoimmune arthritis. We propose in Aim 1 to examine the effect of Rac2 on alphavbeta3 and alpha4beta1 integrin signaling and migration in macrophages and non-hematopoietic cells in an effort to examine the specificity of Rac2 signaling in blood cells. We will examine blood specific upstream effectors of integrin signaling as possible components of a Rac2-dependent integrin-induced signaling complex in macrophages. In Aim 2 we will generate a Rac2 deficient collagen-induced arthritis model in DBA/1 mice to evaluate the contribution of Rac2 to autoimmunity mediated through control of inflammation and angiogenesis. These combined studies will potentially identify novel targets for development of anti-inflammatory agents for the treatment of arthritis and other autoimmune diseases.