Regulation of Mast Cell Function by Inhibitory Molecules

抑制分子对肥大细胞功能的调节

• 批准号: 7759222
• 负责人: Anna Huttenlocher
• 金额: $ 30.58万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759222
• 关键词: Affinity; Allergic; Amino Acids; Arthritis; Attenuated; Autoimmunity; Bacterial Infections; Basophils; Biochemical; Cell Surface Receptors; Cell physiology; Cells; Disease; Dominant-Negative Mutation; Exhibits; Family; Family member; Fc Receptor; Genes; Genetic; Goals; HC phosphatase; Host Defense; Human; IgE; IgE Receptors; IgG Receptors; Immune response; Immune system; In Vitro; Individual; K/BxN model; Mediating; Molecular; Multiple Sclerosis; Mus; PTPN11 gene; Parasitic infection; Pathogenesis; Pathway interactions; Patients; Prevention; Process; Regulation; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Surface; Testing; Therapeutic Intervention; Time; Tyrosine; allergic response; attenuation; base; human disease; in vivo; inositol-1,4,5-trisphosphate 5-phosphatase; insight; leukemia; mast cell; member; mouse model; novel; receptor; research study; response; therapeutic development; treatment strategy

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.

肥大细胞以其在IgE依赖性过敏反应中的作用和宿主防御的作用而受到认可 寄生虫感染。但是，最近的几项研究导致这种观点的扩展，以包括角色 肥大细胞在对细菌感染的正常免疫反应中，最近， 自身免疫发病机理中的肥大细胞（例如关节炎，多发性硬化症）。这些的总体目标 研究是为了定义肥大细胞中的抑制信号传导途径，这可能是 治疗自身免疫和特应性疾病的治疗干预。它变得越来越 清楚地表明，肥大细胞激活受到不断增长的抑制性家族的成员的负调节 受体。该家族中最有特征的成员是fcgammariib，这是IgG的低亲和力受体。 Fcgammariib介导的抑制性信号在调节免疫反应中的重要性很明显 Fcgammariib缺陷小鼠，表现出增强的过敏反应和自身免疫性。最近的 研究进一步表明，fcgammariib抑制信号由肌醇5-介导 磷酸酶船。几项研究暗示了船舶抑制活性在预防人类疾病中。 具体而言，在过敏个体的LGE+嗜碱性粒细胞中观察到船舶表达降低， 在来自CML患者的原发性白血病细胞中。另外，船的主要负突变 来自AML患者的原发性白血病细胞中鉴定了基因。拟议的研究将利用 遗传，生化和细胞方法来定义船舶调节的分子机制 肥大细胞激活。该提议的具体目的是i）剖析分子机制 船只调节FC受体介导的肥大细胞激活，ii）确定船在转导中的作用 MAIR-1下游的抑制信号，Mair-1，一种在肥大细胞中表达的新型抑制受体，iii）定义 使用鼠标模型，船，fcgammariib和Mair-1在体内调节肥大细胞功能中的作用 人类类风湿关节炎。这些目标的成功完成将为您提供新的见解 船体调节肥大细胞功能的机制，这可能在开发中有用 治疗arhtritis和特应性疾病的治疗策略。