Rac2 in integrin macrophage function

我们实验室的初步数据已经证实，在rac2-/-小鼠体内，αvbeta3和alpha4beta1整合素引导的Vitronectin巨噬细胞迁移存在明显的缺陷。αvbeta3和alpha4beta1整合素介导炎症的重要成分。巨噬细胞必须使用αv整合素迁移到炎症部位，在那里它们调节炎症和血管生成。此外，αv整合素与基质降解酶、基质金属蛋白酶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，是伤口愈合、炎症和血管生成的必要组成部分。最近的证据表明，αβ3整合素是自身免疫性关节炎的重要组成部分，阻断αβ3(功能阻断单抗、LM609和/或RGD多肽)的药物可以改善关节炎状态。炎症和血管生成都是自身免疫性关节炎发病机制的重要组成部分。在目标1中，我们建议检测rac2对αvbeta3和alpha4beta1整合素信号的影响以及在巨噬细胞和非造血细胞中的迁移，以努力检测在血细胞中rac2信号的特异性。我们将研究血液中特异的整合素信号上游效应器，作为巨噬细胞中依赖于rac2的整合素诱导的信号复合体的可能组成部分。在目标2中，我们将在DBA/1小鼠中建立一个rac2缺陷型胶原诱导的关节炎模型，以评估rac2在通过控制炎症和血管生成而介导的自身免疫中的作用。这些联合研究将有可能确定用于治疗关节炎和其他自身免疫性疾病的抗炎药开发的新靶点。

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.