IGC REGULATION OF IGE-MEDIATED BASOPHIL DEGRANULATION

描述：(改编自调查者摘要)将变应原结合到 Ige与肥大细胞上的高亲和力受体(FceRI)络合， 嗜碱性粒细胞启动组胺和其他介质的释放。这些 特应症的各种表现在很大程度上要由调解人负责。 影响20%以上人口的疾病。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 脱颗粒受到强有力的负性调节，通过与 共表达的Ig G Fc、FcgRIIB受体，并且，进一步地，这种效应是 由FcgRIIB1酪氨酸磷酸化介导的募集和 胞质磷酸酪氨酸磷酸酶PTP1C和PTP1D的激活。 目标1中提出的研究将确定哪些FcgRIIB1亚型是 在人血嗜碱性粒细胞中表达并在抑制信号中起作用。 AIM 2的研究将评估和定位FcgRIIB的酪氨酸磷酸化 并确定与磷酸化受体结合的潜在效应物。 目标3将确定这些效应器的作用，最明显的是PTP1C和PTP1D， 在抑制信号转导中，Aim 4将确定 PTP1C和PTP1D(或其他相关效应因子)在FceRI中的作用 信号转导途径。拟议的研究将利用当代 细胞生物学和生化方法，以及突变分析 确定结构-功能关系和受体重构以 建立FcgRIIB介导的抑制信号转导机制。最后， PTP1C阴性小鼠(母鼠)和PTP1D来源的肥大细胞 敲除胚胎干细胞和这些酶的显性负性突变体 将被用来确认酶在FcgRIIB效应中的作用。研究 基于受体结构合成的磷酸肽的作用能力 激活PTP1C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.