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Regulation of Mast Cell Function by Inhibitory Molecules

抑制分子对肥大细胞功能的调节

基本信息

批准号：
7356009
负责人：
Anna Huttenlocher
金额：
$ 30.92万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/7356009
关键词：
Affinity Allergic Amino Acids Arthritis Attenuated Autoimmunity Bacterial Infections Basophils Biochemical Biochemical Genetics Cell Surface Receptors Cell physiology Cells Development Disease Dominant-Negative Mutation Exhibits Family Family member Fc Receptor Genes Goals HC phosphatase Host Defense Human IgE IgE Receptors IgG Receptors Immune response Immune system In Vitro Individual Inflammation Joints 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 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

项目摘要

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.

肥大细胞因其在ige依赖性过敏反应和宿主防御中的作用而被公认