Research Project 1: Systems level complexity of ITAM signaling

项目 1：ITAM 信令的系统级复杂性 项目负责人：Wilson 总结 T细胞、B细胞、肥大细胞、嗜碱性粒细胞、树突状细胞等免疫细胞的重要免疫受体 细胞质尾部带有 ITAM（基于免疫酪氨酸的激活基序）。酪氨酸磷酸化后 通过 Src 激酶，磷酸化 ITAM 招募 Syk/ZAP-70 激酶来传播与 关键的适应性和先天免疫功能。在这个项目中，STMC 研究人员应用了多尺度系统 生物学方法评估空间组织和配体多价对 ITAM 受体的贡献 信号启动和输出。 Aim 1 的模型系统是受体 (FceRI) 的高亲和力受体 肥大细胞和嗜碱性粒细胞。创新重点是基于人体实验的天然过敏原 来自特应性受试者的嗜碱性粒细胞。目标 2 以 C 型凝集素受体 Dectin-1 为中心，该受体识别 真菌病原体。高分辨率显微镜方法，结合配体的定量评估 介导的聚集，是两个实验目标的新颖特征。该研究计划包含广泛 计算建模，包括分子结构/动力学和细胞信号转导的模拟。 数学模型将提供预测，通过强大的创新应用进行测试 定量荧光、电子显微镜和分子工程方法。

Project 1: Systems level complexity of ITAM signaling Project PI: Wilson Summary Important immunoreceptors of T cells, B cells, mast cells, basophils, dendritic cells and other immune cells bear ITAMs (Immuno Tyrosine-Based Activation Motif) in their cytoplasmic tails. After tyrosine phosphorylation by Src kinases, phospho-ITAMs recruit Syk/ZAP-70 kinases to propagate positive signaling associated with key adaptive and innate immune functions. In this project, STMC investigators apply a multiscale systems biology approach to evaluate the contributions of spatial organization and ligand multivalency on ITAM receptor signal initiation and output. The model system for Aim 1 is the high affinity receptor for receptor (FceRI) on mast cells and basophils. An innovative focus is on natural allergens, based on experiments in human basophils from atopic subjects. Aim 2 is centered on the C-type lectin receptor, Dectin-1, that recognizes fungal pathogens. High resolution microscopy methods, coupled with quantitative evaluation of ligand- mediated aggregation, are novel features of both experimental aims. The research plan incorporates extensive computational modeling, including molecular structure/dynamics and simulations of cellular signal transduction. Mathematical models will provide predictions to be tested through the innovative application of powerful quantitative fluorescence, electron microscopy and molecular engineering methods.