IGC REGULATION OF IGE-MEDIATED BASOPHIL DEGRANULATION

描述：（改编自研究者摘要）过敏原与 IgE与肥大细胞上的高亲和力受体（FceRI）复合， 嗜碱性粒细胞启动组胺和其它介质的释放。 这些 介质主要负责特应性的各种表现， 这种疾病影响了超过20%的人口。 基于 最近的发现，我们假设FceRI介导的嗜碱性粒细胞和肥大细胞 脱粒受到通过与一种 共表达的IgG Fc受体、FcgRIIB，并且进一步地，这种作用是 由FcgRIIB 1酪氨酸磷酸化介导，导致募集， 细胞质磷酸酪氨酸磷酸酶PTP 1C和PTP 1D的活化。 目的1中提出的研究将确定哪些FcgRIIB 1同种型是 在人血液嗜碱性粒细胞中表达并在抑制信号传导中起作用。 目标2中的研究将评估和绘制FcgRIIB中的酪氨酸磷酸化。 并鉴定结合磷酸化受体的潜在效应物。 目标3将定义这些效应物的作用，最值得注意的是PTP 1C和PTP 1D， 在抑制信号传导中，Aim 4将确定 PTP 1C和PTP 1D（或其他相关效应物）在FceRI中的作用 信号转导途径 拟议的研究将利用当代 细胞生物学和生物化学方法，沿着突变分析 定义结构-功能关系，以及受体重建， 建立FcgRIIB介导的抑制性信号传导机制。 最后， 来源于PTP 1C阴性小鼠（虫蛀小鼠）和PTP 1D的肥大细胞 敲除胚胎干细胞和这些酶的显性失活突变体 将用于确认酶在FcgRIIB效应中的作用。 研究 基于受体结构合成的磷酸肽， 激活PTP 1C和抑制FceRI功能可能导致新的 特应性疾病的治疗方法。

DESCRIPTION: (Adapted from Investigator's abstract) Binding of allergen to IgE complexed to its high affinity receptors (FceRI) on mast cells and basophils initiates release of histamine and other mediators. These mediators are largely responsible for the various manifestations of atopic disease which affects more than 20% of the human population. Based on recent findings, we hypothesize that FceRI mediated basophil and mast cell degranulation is subject to potent negative regulation by co-ligation with a coexpressed receptor for IgG Fc, FcgRIIB, and, further, that this effect is mediated by FcgRIIB1 tyrosine phosphorylation leading to recruitment and activation of the cytoplasmic phosphotyrosine phosphatase PTP1C and PTP1D. Studies proposed in Aim 1 will determine which FcgRIIB1 isoforms are expressed and operative in inhibitory signaling in human blood basophils. Studies in Aim 2 will assess and map tyrosine phosphorylation in the FcgRIIB and identify potential effectors which bind the phosphorylated receptor. Aim 3 will define the role of these effectors, most notably PTP1C and PTP1D, in inhibitory signaling, and Aim 4 will identify the molecular site of action of PTP1C and PTP1D (or other implicated effectors) in the FceRI signal transduction pathway. The proposed studies will utilize contemporary cell biological and biochemical approaches, along with mutational analysis to define structure-function relationships, and receptor reconstitution to establish the mechanism of FcgRIIB-mediated inhibitory signaling. Finally, mast cells derived from PTP1C negative mice (motheaten mice) and PTP1D knockout embryonal stem cells and dominant negative mutants of these enzymes will be used to confirm the role of enzymes in the FcgRIIB effect. Studies of the ability of phosphopeptides synthesized based on receptor structure to activate PTP1C and inhibit FceRI function may lead to development of new therapeutic approaches in atopic disease.