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: 7559542
• 负责人: Anna Huttenlocher
• 金额: $ 30.91万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559542
• 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; 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.

肥大细胞在IgE依赖性过敏反应和宿主防御中的作用是最被认可的。 寄生虫感染然而，最近的几项研究已经扩大了这一观点，包括作用 肥大细胞在对细菌感染的正常免疫反应中的作用，以及最近， 肥大细胞在自身免疫发病机制中的作用（例如关节炎、多发性硬化）。这些活动的总体目标 研究的目的是确定肥大细胞中的抑制性信号通路，这些通路可能作为 在治疗自身免疫和特应性疾病中的治疗性干预。已变得越来越 清楚肥大细胞活化受到生长中的抑制性肥大细胞家族成员的负调节， 受体。该家族最具特征的成员是Fc γ RIIB，IgG的低亲和力受体。 Fc γ RIIB介导的抑制信号在调节免疫应答中的重要性是明显的， Fc γ RIIB缺陷小鼠，其表现出增强的过敏反应和自身免疫。最近 研究进一步证明Fc γ RIIB抑制信号由肌醇5- 磷酸酶SHIP。几项研究表明SHIP抑制活性可预防人类疾病。 具体而言，在过敏个体的IgE+嗜碱性粒细胞中观察到SHIP表达降低， 在CML患者的原代白血病细胞中。此外，SHIP基因的显性负突变 在来自AML患者的原代白血病细胞中鉴定了基因。拟议的研究将利用 遗传，生物化学和细胞方法来定义SHIP调节的分子机制 肥大细胞活化本提案的具体目标是：i）剖析 SHIP调节Fc受体介导的肥大细胞活化，ii）确定SHIP在转导中的作用， MAIR-1下游的抑制性信号，MAIR-1是肥大细胞中表达的一种新的抑制性受体，和iii）定义 SHIP、Fc γ RIIB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新的视角， SHIP调节肥大细胞功能的机制可能对肥大细胞的发育有用 治疗关节炎和特应性疾病的治疗策略。