Mouse Mast Cell Inhibitory Receptors of the gp49 Family

由先天和获得性免疫反应引发的炎症是生存的重要组成部分，但过度侵略性的炎症反应是有害的。免疫系统调节这种微妙平衡的生化和分子机制还不是很清楚。细胞表面受体gp49B1在体内抑制肥大细胞(MC)和中性粒细胞对先天或获得性免疫系统效应刺激的病理性激活。然而，我们对gp49B1如何在体内抑制不同药物诱导的细胞激活的机制知之甚少。这项研究的长期目标是了解gp49B1如何在哮喘等炎症性疾病中控制肺部和其他器官的炎症。为了确定当gp49B1抑制MC激活时发生的生化和分子事件，我们将检验这样一个中心假设：MC与某些细胞外基质(ECM)成分的结合为其抑制功能准备或“启动”了gp49B1，而可溶性激活剂通过诱导启动的丝氨酸磷酸化来实现。 Gp49B1调节gp49B1抑制激活受体发出的信号的能力。我们将通过追求以下具体目标来检验中心假设：1)确定ECM在启动gp49B1抑制功能中的作用。我们将确定相关的细胞外基质分子，巨噬细胞表面分子的受体，以及相互作用诱导gp49B1启动的生化机制。2)建立启动gp49B1抑制激活信号和功能的机制。我们将确定当体外用gp49B1抑制的药物激活MC时，细胞外基质诱导的gp49B1抑制的激活信号步骤和炎症介质。3)探讨gp49B1丝氨酸磷酸化在抑制细胞活化中的作用。我们将确定丝氨酸磷酸化在调节启动的gp49B1抑制能力中的作用，并确定参与其中的丝氨酸(S)和激酶{S]。这项拟议的研究最终将带来的好处有望包括认识到gp49B1相关的人类抑制受体和/或相互作用分子的结构和表达的遗传差异如何与炎症性肺病的发生率、严重性和预后有关。

Inflammation initiated by innate and adaptive immune responses is an essential component for survival, yet overly aggressive inflammatory responses are detrimental. The biochemical and molecular mechanisms by which the immune system regulates this delicate balance are not well understood. The cell surface receptor gp49B1 inhibits the pathologic activation of mast cells (MCs) and neutrophils in response to effector stimuli of either the innate or adaptive immune systems in vivo. However, we have little mechanistic understanding of how gp49B1 inhibits cell activation induced by diverse agents in vivo. The long-term goal of this research is to understand how gp49B1 controls inflammation in the lung and other organs in inflammatory diseases such as asthma. To define the biochemical and molecular events that transpire when gp49B1 inhibits MC activation, we will test the central hypothesis that the binding of MC to certain extracellular matrix (ECM) components prepares or "primes" gp49B1 for its inhibitory function, and that soluble activating agents, by inducing serine phosphorylation of primed gp49B1, modulate the ability of gp49B1 to inhibit signals emanating from activating receptors. We will test the central hypothesis by pursuing the following Specific Aims: 1) To establish the role of ECM in priming gp49B1 for inhibitory function. We will identify the relevant ECM molecules, the receptors for the molecules on MCs, and the biochemical mechanism by which the interactions induce the priming of gp49B1. 2) To establish the mechanism by which primed gp49B1 inhibits activation signaling and function. We will identify the activation signaling steps and inflammatory mediators inhibited by ECM-primed gp49B1 when MCs are activated in vitro with agents that are inhibited by gp49B1 in vivo. 3) To establish the role of serine phosphorylation of primed gp49B1 in the inhibition of cell activation. We will determine the role of serine phosphorylation in modulating the inhibitory capacity of primed gp49B1 and identify the serine(s) and kinase{s) involved. The benefits that will ultimately accrue from the proposed research are expected to include the recognition of how genetic differences in the structure and expression of gp49B1-related human inhibitory receptors and/or interacting molecules relate to the incidence, severity, and prognosis of inflammatory pulmonary.