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

摘要/摘要 本项目的重点是肥大细胞(MC)增殖、异质性和 慢性鼻窦炎合并鼻息肉(CRSwNP)的激活，尤其是在阿司匹林中 急性呼吸道疾病(AERD)。AADCRC目前迭代的研究表明， 典型的肥大细胞亚型表达类胰蛋白酶和糜酶(MCTC)或单独表达类胰蛋白酶(MCT) 新的CD117hiCD38在过渡MC人群中具有丰富的增殖和激活标志。 新的数据表明，成纤维细胞衍生的因子推动了这种增殖的MC群体的出现 循环MC祖细胞和基质细胞与细胞因子(特别是IL-4Rα活性)共谋 细胞因子和IL-33)在相应不同的解剖结构中驱动不同的MC效应功能 鼻腔粘膜的隔室。一种结合功能研究的无监督网络分析 一种新的三维培养系统揭示了MC来源的LIF和LIF之间可能的前馈系统 成纤维细胞来源的IL-6可能促进MC的扩张和激活，并受到IL-4Rα的极大促进 MC和成纤维细胞上的信号转导。该项目结合了假设检验和无偏见的方法 了解巨噬细胞的发育起源，巨噬细胞在T2I中扩张和激活的功能控制， 在此背景下，MC进而影响基质细胞功能的机制。从长远来看， 目标是准确地识别最有责任驱动MC的细胞内在和外在因素 并影响其在呼吸系统T2I的效应功能，以了解局部后果 MC对组织功能的影响，并找出潜在的治疗靶点。目标一号将绘制分子图 循环单核细胞趋化蛋白及其可能的组织后代之间的转变和决定发育的 富含增殖的过渡性MC的起源。目标2将确定成纤维细胞和 内皮祖细胞促进上皮下巨噬细胞和移行巨噬细胞的发育并增强其活化 T2I的设置。目标3将确定基质细胞扩增的MC衍生介质的作用，包括LIF， 在T2I中驱动MC-基质细胞的相互作用。该项目是AADCRC总体目标的组成部分，以及 涉及到与其他两个项目的实质性互动。

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.