Regulation of Mast Cell Function by Inhibitory Molecules

肥大细胞在IgE依赖的过敏反应和宿主防御中的作用最为人所知 寄生虫感染。然而，最近的几项研究导致了这一观点的扩展，将角色包括在内 肥大细胞在正常的免疫反应中对细菌感染的作用以及最近， 肥大细胞在自身免疫(如关节炎、多发性硬化症)发病机制中的作用。这些项目的总体目标是 研究是确定肥大细胞中可能作为潜在靶点的抑制信号通路 自身免疫和特应性疾病治疗中的治疗干预。它已经变得越来越多 明确肥大细胞的激活受制于一个不断增长的抑制性家族成员的负面调节 感受器。这个家族中最典型的成员是FcGammaRIIB，它是一种低亲和力的免疫球蛋白受体。 FcGammaRIIB介导的抑制信号在调节免疫反应中的重要性是显而易见的 FcGammaRIIB缺陷小鼠，表现出增强的过敏反应和自身免疫。近期 研究进一步证明，FcGammaRIIB抑制信号是由肌醇5- 磷酸酶船。几项研究表明，船舶抑制活性在预防人类疾病中具有一定的作用。 具体地说，已经观察到过敏个体的LGE+嗜碱性粒细胞中SHIP表达减少。 在慢性粒细胞白血病患者的原代白血病细胞中。此外，该船的一个显性负突变 在1例急性髓系白血病患者的原代白血病细胞中发现了该基因。拟议的研究将利用 用遗传、生化和细胞方法定义SHIP调节的分子机制 肥大细胞激活。这项提议的具体目的是：1)剖析分子机制 SHIP调节Fc受体介导的肥大细胞激活，II)确定SHIP在信号转导中的作用 Mair-1下游的抑制信号，Mair-1是一种在肥大细胞中表达的新的抑制受体，并且iii)定义 SHIP、FcGammaRIIB和Mair-1在体内调节肥大细胞功能中的作用 人类类风湿性关节炎。这些目标的成功实现将为我们提供对 船舶调节肥大细胞功能的机制，这可能有助于 治疗关节炎和特应性疾病的治疗策略。

Mast cells are most recognized for their role in IgE-dependent allergic responses and host defense against parasitic infection. However, several recent studies have led to an expansion of this view to include the role of mast cells in the normal immune response to bacterial infection and most recently, the profound role of mast cells in the pathogenesis of autoimmunity (e.g. arthritis, multiple sclerosis). The overall goal of these studies is to define inhibitory signaling pathways in mast cells that may serve as potential targets for therapeutic intervention in the treatment of autoimmunity and atopic disease. It has become increasingly clear that mast cell activation is subject to negative regulation by members of a growing family of inhibitory receptors. The most characterized member of this family is FcgammaRIIB, the low-affinity receptor for IgG. The importance of FcgammaRIIB-mediated inhibitory signals in regulating immune responses is evident in FcgammaRIIB-deficient mice, which exhibit enhanced anaphylactic responses and autoimmunity. Recent studies have further demonstrated that FcgammaRIIB inhibitory signals are mediated by the inositol 5- phosphatase SHIP. Several studies implicate SHIP inhibitory activity in the prevention of human disease. Specifically, decreased SHIP expression has been observed in lgE+ basophils from allergic individuals and in primary leukemia cells from patients with CML. In addition, a dominant negative mutation of the SHIP gene was identified in primary leukemia cells from a patient with AML. The proposed studies will utilize genetic, biochemical, and cellular approaches to define the molecular mechanisms by which SHIP regulates mast cell activation. The specific aims of this proposal are to i) dissect the molecular mechanisms by which SHIP regulates Fc receptor-mediated mast cell activation, ii) determine the role of SHIP in transducing inhibitory signals downstream of MAIR-1, a novel inhibitory receptor expressed in mast cells, and iii) define the role of SHIP, FcgammaRIIB, and MAIR-1 in regulating mast cell function in vivo using a mouse model of human rheumatoid arthritis. The successful completion of these aims will provide new insights into the mechanisms by which SHIP regulates mast cell function which may be useful in the development of therapeutic strategies for the treatment of arhtritis and atopic disease.