GP49 FAMILY MEDIATED INTERACTIONS IN THE IMMUNE SYSTEM

描述(改编自调查人员摘要)：肥大细胞具有高 促炎作用，因为它们含有大量生物活性物质 三类介质：预制的、分泌颗粒衍生的介质 如组胺和蛋白水解酶；新产生的脂质介质，如 白三烯C4(LTC4)、前列腺素D2和血小板活化因子； 以及包括IL-1B、IL-6和TNF-α在内的一整套促炎细胞因子。 肥大细胞，驻留在正常组织中，位于自身和 非我，必须严格监管，以防止 先天的或免疫的激活。事实上，不适当地激活桅杆 细胞会导致即刻的过敏反应和哮喘。 研究人员发现了小鼠肥大细胞gp49并对其进行了鉴定。 基因家族，这是免疫球蛋白超家族的一部分。这个 该家族的一个成员gp49B1的胞质结构域包含两个 免疫受体酪氨酸抑制基序(ITIMs)。他向我们展示了 Gp49B1与肥大细胞表面高亲和力IgE受体(FceRI)的交联 细胞抑制组胺和B-氨基己糖苷酶的胞吐，以及 LTC4的产生。因此，gp49B1是一种新发现的 肥大细胞激活的反向调节因子。然而，机制(S)由 哪种gp49B1抑制肥大细胞的激活是已知的，这是自然的 Gp49B1的配体(“gp49B1L”)。拟议研究的总体目标 是为了更多地了解gp49B1的细胞和分子生物学 肥大细胞，长期目标是利用其配体驱动的 控制有害肥大细胞激活的抑制途径 过敏反应在哮喘发病机制中的作用 以及其他形式的炎症。该应用程序建议实现 通过追求以下具体目标，实现其广泛目标的第一阶段： 1)明确gp49B1抑制信号转导的分子机制(S 导致肥大细胞激活的转导途径；以及2)克隆， 鉴定和表达gp49B1L，以确定其生物学意义 它与gp49B1的相互作用。

DESCRIPTION (Adapted from Investigator's abstract): Mast cells have high proinflammatory potential because they contain a large number of bioactive mediators of three classes: preformed, secretory granule-derived mediators such as histamine and proteases; newly generated lipid mediators such as leukotriene C4 (LTC4), prostaglandin D2, and the platelet-activating factor; and a panoply of proinflammatory cytokines including IL-1B, IL-6, and TNF-a. Mast cells, which reside in normal tissues at the interface between self and non-self, must be tightly regulated to prevent the deleterious effects of innate or immunologic activation. Indeed, inappropriate activation of mast cells leads to immediate hypersensitivity reactions and bronchial asthma. The investigator has discovered and characterized the mouse mast cell gp49 gene family, which is part of the Immunoglobulin Superfamily. The cytoplasmic domain of one member of the family, gp49B1, contains two Immunoreceptor Tyrosine-based Inhibition Motifs (ITIMs). He showed that the cross-linking of gp49B1 with the high affinity IgE receptor (FceRI) on mast cells inhibits the exocytosis of histamine and B-hexosaminidase, as well as the generation of LTC4. Thus, gp49B1 is a newly recognized counter-regulator of mast cell activation. However, the mechanism(s) by which gp49B1 inhibits mast cell activation is known, as is the natural ligand for gp49B1 ("gp49B1L"). The broad objective of the proposed research is to understand more about the cellular and molecular biology of gp49B1 in mast cells, with the long range goal of harnessing its ligand-driven inhibitory pathway to control deleterious mast cell activation that causes allergic reactions and contributes to the pathogenesis of bronchial asthma and other forms of inflammation. The application proposes to achieve the first stage of its broad objective by pursuing the following Specific Aims: 1) to define the molecular mechanism(s) by which gp49B1 inhibits the signal transduction pathways leading to mast cell activation; and 2) to clone, characterize, and express gp49B1L so as to define the biologic significance of its interaction with gp49B1.