Mouse Mast Cell Inhibitory Receptors of the gp49 Family

gp49 家族的小鼠肥大细胞抑制性受体

• 批准号: 7422405
• 负责人: HOWARD R KATZ
• 金额: $ 45.56万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7422405
• 关键词: Asthma; Binding; Biochemical; Cell Surface Receptors; Cells; Disease; Equilibrium; Event; Extracellular Matrix; Family; Genetic; Goals; Human; Immune response; Immune system; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Lung; Mediator of activation protein; Molecular; Mus; Organ; Pathologic; Phosphorylation; Protein-Serine-Threonine Kinases; Research; Role; Serine; Severities; Signal Transduction; Stimulus; Structure; Testing; in vivo; mast cell; neutrophil; outcome forecast; receptor; response

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.

由先天性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物化学和分子机制还不清楚。细胞表面受体gp 49 B1抑制肥大细胞（MC）和中性粒细胞响应体内先天性或适应性免疫系统的效应刺激的病理性活化。然而，我们对gp 49 B1如何抑制体内不同药物诱导的细胞活化的机制了解甚少。这项研究的长期目标是了解gp 49 B1如何控制哮喘等炎症性疾病中肺部和其他器官的炎症。为了确定当gp 49 B1抑制MC活化时发生的生物化学和分子事件，我们将检验中心假设，即MC与某些细胞外基质（ECM）组分的结合准备或“引发”gp 49 B1的抑制功能，并且可溶性活化剂通过诱导引发的细胞外基质（ECM）组分的丝氨酸磷酸化， gp 49 B1调节gp 49 B1抑制从活化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在引发gp 49 B1抑制功能中的作用。我们将确定相关的ECM分子，MC上的分子受体，以及相互作用诱导gp 49 B1启动的生化机制。2)建立引发的gp 49 B1抑制活化信号和功能的机制。我们将确定激活信号步骤和炎症介质抑制ECM引发的gp 49 B1时，MC在体外激活的药物，在体内抑制gp 49 B1。3)确定引发的gp 49 B1的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引发的gp 49 B1的抑制能力中的作用，并鉴定所涉及的丝氨酸和激酶。预计最终将从拟议的研究中获得的益处包括认识到gp 49 B1相关的人类抑制性受体和/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部疾病的发病率，严重程度和预后相关。