Regulation of Mast Cell Function by Inhibitory Molecules

描述(由申请人提供)：肥大细胞在IgE依赖的过敏反应和宿主防御寄生虫感染中的作用是最受认可的。这些研究的总体目标是确定肥大细胞中的抑制信号通路，这些信号通路可能成为自身免疫和特应性疾病治疗干预的潜在靶点。越来越清楚的是，肥大细胞的激活受到越来越多的抑制性受体家族成员的负面调控。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在FcGammaRIIB缺陷小鼠中是显而易见的，这些小鼠表现出增强的过敏反应和自身免疫。最近的研究进一步证明，FcGammaRIIB抑制信号是由肌醇5-磷酸酶SHIP介导的。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。特别是，在过敏个体的Lge+嗜碱性粒细胞和CML患者的原代白血病细胞中观察到Ship的表达减少。此外，在一名AML患者的原代白血病细胞中发现了SHIP基因的显性负突变。拟议的研究将利用遗传、生化和细胞方法来确定SHIP调节肥大细胞激活的分子机制。这项建议的具体目的是：i)剖析SHIP调节Fc受体介导的肥大细胞激活的分子机制；ii)确定SHIP在肥大细胞表达的一种新的抑制性受体Mair-1下游传递抑制信号中的作用；iii)利用人类类风湿关节炎的小鼠模型，确定Ship、FcGammaRIIB和Mair-1在体内调节肥大细胞功能的作用。这些目标的成功完成将为SHIP调节肥大细胞功能的机制提供新的见解，这可能有助于开发治疗关节炎和特应性疾病的治疗策略。

DESCRIPTION (provided by applicant): 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.