Project 1. Regulation of Mast Cell Homeostasis in Type 2 Immunopathology

摘要/概要 本项目的重点是肥大细胞（MC）增生，异质性， 激活是慢性鼻窦炎鼻息肉病（CRSwNP）的特征，尤其是阿司匹林 急性呼吸道疾病（AERD）。本AADCRC当前迭代中的研究表明， 表达类胰蛋白酶和糜蛋白酶（MCTC）或仅表达类胰蛋白酶（MCT）的典型肥大细胞亚型出现于 新的CD 117 hiCD 38 hi过渡性MC群体，其富含增殖和活化的标志物。 新的数据表明，成纤维细胞衍生因子驱动这种增殖的MC群体的出现， 循环MC祖细胞（MCp），以及基质细胞与细胞因子（特别是IL-4 R α活性 细胞因子和IL-33）驱动相应不同解剖结构中的不同MC效应器功能。 鼻窦粘膜的隔室。无监督网络分析结合功能研究， 一个新的三维培养系统揭示了一个可能的前馈系统之间的MC衍生的LIF和 成纤维细胞来源的IL-6，可促进MC扩增和活化，并由IL-4 R α大大促进 在MC和成纤维细胞上的信号传导。该项目结合了假设检验和无偏见的方法， 了解MC的发育起源，T2 I中MC扩张和激活的功能控制， 以及在这种情况下MC反过来影响基质细胞功能的机制。长期总体 目标是精确地识别最负责驱动MC的细胞内在和外在因素 增生和影响其效应器功能在呼吸T2 I，了解局部后果 MC增生的组织功能，并确定潜在的治疗靶点。目标1将绘制分子图 循环MCp与其推定的组织后代之间的过渡，并决定发育 增殖富集的过渡MCs的起源。目的2将确定成纤维细胞和 EpCs促进上皮下MCTC和移行MCs的发育，并增强其在细胞内的活化。 设置T2 I。目的3将确定基质细胞扩增的MC衍生介质的作用，包括LIF， 在T2 I中驱动MC-基质细胞相互作用。该项目是AADCRC总体目标的组成部分， 与其他两个项目有很大的互动。

Abstract/Summary This Project focuses on the mechanisms responsible for mast cell (MC) hyperplasia, heterogeneity, and activation that are characteristic of chronic rhinosinusitis with nasal polyposis (CRSwNP), especially in aspirin exacerbated respiratory disease (AERD). Studies in the current iteration of this AADCRC suggest that canonical mast cell subtypes expressing tryptase and chymase (MCTC) or tryptase alone (MCT) emerge from a novel CD117hiCD38hi transitional MC population that is enriched for markers of proliferation and activation. New data suggest that fibroblast-derived factors drive the emergence of this proliferating MC population from circulating MC progenitors (MCp), and that stromal cells conspire with cytokines (particularly IL-4Rα-active cytokines and IL-33) to drive different MC effector functions in correspondingly different anatomic compartments of the sinonasal mucosa. An unsupervised network analysis combined with functional studies in a novel 3-dimensional culture system reveals a likely feed-forward system between MC-derived LIF and fibroblast-derived IL-6 that may promote MC expansion and activation, and is greatly facilitated by IL-4Rα signaling at both MCs and fibroblasts. This Project combines hypothesis-testing and unbiased approaches to understand the developmental origins of MCs, the functional control of MC expansion and activation in T2I, and the mechanisms by which MCs in turn influence stromal cell function in this context. The long-term overall goals are to precisely identify the cell-intrinsic and -extrinsic factors most responsible for driving MC hyperplasia and influencing their effector function in respiratory T2I, to understand the local consequences of MC hyperplasia in tissue function, and to identify potential therapeutic targets. Aim 1 will map the molecular transitions between circulating MCp and their putative tissue descendants and determine the developmental origins of proliferation-enriched transitional MCs. Aim 2 will identify the mechanisms by which fibroblasts and EpCs facilitate the development of subepithelial MCTC and transitional MCs and potentiate their activation in the setting of T2I. Aim 3 will determine the role of stromal cell-amplified MC-derived mediators, including LIF, in driving MC-stromal cell interactions in T2I. The project is integral to the overall goals of the AADCRC, and involves substantial interactions with the other two Projects.