Mouse Mast Cell Inhibitory Receptors of the gp49 Family

由先天和适应性免疫反应引发的炎症是生存的重要组成部分，但过度积极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尚不清楚。细胞表面受体gp49B1抑制肥大细胞（MCs）和中性粒细胞的病理激活，以响应先天或适应性免疫系统的效应刺激。然而，我们对gp49B1如何在体内抑制多种药物诱导的细胞活化的机制知之甚少。这项研究的长期目标是了解gp49B1如何控制哮喘等炎症性疾病中肺部和其他器官的炎症。为了确定gp49B1抑制MC激活时发生的生化和分子事件，我们将验证一个中心假设，即MC与某些细胞外基质（ECM）成分的结合，通过诱导引物的丝氨酸磷酸化，为gp49B1的抑制功能和可溶性激活剂做好准备或“引物”

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.