GP49 FAMILY MEDIATED INTERACTIONS IN THE IMMUNE SYSTEM

描述（改编自研究者摘要）：肥大细胞具有较高的 促炎潜力，因为它们含有大量的生物活性 三种类型的介质：预先形成的、分泌颗粒衍生的介质 如组胺和蛋白酶;新产生的脂质介质， 白三烯C4（LTC 4）、前列腺素D2和血小板活化因子; 以及一系列促炎细胞因子，包括IL-1B、IL-6和TNF-α。 肥大细胞存在于正常组织中，位于自身和 非自我，必须严格管制，以防止有害的影响， 先天或免疫激活。 事实上，不适当的启动桅杆 细胞导致速发型超敏反应和支气管哮喘。 研究者发现并鉴定了小鼠肥大细胞gp 49 基因家族，其是免疫球蛋白超家族的一部分。 的 该家族的一个成员gp 49 B1的胞质结构域包含两个 基于免疫受体酪氨酸的抑制基序（ITIM）。 他表示， gp 49 B1与肥大细胞上的高亲和力IgE受体（FceRI）的交联 细胞抑制组胺和B-氨基己糖苷酶的胞吐作用，以及 LTC 4代。 因此，gp 49 B1是一个新认识的 肥大细胞活化的反调节剂。 然而， gp 49 B1抑制肥大细胞活化的机制是已知的， gp 49 B1的配体（“gp 49 B1 L”）。 拟议研究的广泛目标 是了解更多关于gp 49 B1的细胞和分子生物学， 肥大细胞，其长期目标是利用其配体驱动的 抑制途径来控制有害肥大细胞活化， 过敏反应，并有助于支气管哮喘的发病机制 和其他形式的炎症。 该申请建议实现 第一阶段的广泛目标是实现以下具体目标： 1)为了定义gp 49 B1抑制信号的分子机制， 导致肥大细胞活化的转导途径;和2）克隆， 表征并表达gp 49 B1 L，以确定其生物学意义 它与gp 49 B1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.