Mobilization and trafficking of central ILC progenitors

中央 ILC 祖细胞的动员和贩运

基本信息

批准号：
10732869
负责人：
CHANG H KIM
金额：
$ 30.89万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-01-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY Innate lymphoid cells (ILCs) are an essential part of peripheral tissues by regulating tissue homeostasis, immunity and inflammation. Peripheral ILC populations undergo spontaneous and induced attrition over time and should be replenished to maintain their normal numbers and subset composition. Bone marrow (BM) is the major site that produces ILC progenitors for peripheral tissues. The first step to deliver ILC progenitors into peripheral tissues is the mobilization of ILC progenitors from the BM, and this presumably requires regulated emigration of ILC progenitors from the BM and their ultimate trafficking into various peripheral tissues. Unfortunately, we hardly understand how various ILC progenitors are mobilized from the BM and characteristically distributed to various peripheral tissues in steady state and how these processes are altered in inflammatory conditions. The overarching objective of this project is to understand the mobilization and trafficking of BM ILC progenitors. Several important questions arise in terms of the mobilization and migration of central ILC progenitors: Which progenitors dominantly emigrate from BM to generate peripheral ILC subsets? Are they multi-potential and/or committed progenitors? What are the mechanisms and signals that trigger their emigration? How do these progenitor cells in the blood circulation enter distinct peripheral tissues? Is the migration mechanism universal or specific for each progenitor subset or tissue site? How do inflammatory signals alter the mobilization and migration patterns of ILC progenitors, and can we control tissue ILC activity in pathogenic conditions by utilizing mobilized BM ILC progenitors or targeting their mobilization and migration? We devised the following specific aims to investigate these questions regarding the mobilization and trafficking of ILC progenitors. Aim 1. Identify the underlying mechanism for the retention vs. emigration of BM ILC progenitors; Aim 2. Investigate how the retention vs. emigration of BM ILC progenitors is regulated by the circadian rhythm; Aim 3. Identify inflammatory signals that regulate the retention vs. emigration of BM ILC progenitors; Aim 4. Identify the homing behavior and trafficking receptors of emigrated ILC progenitors. The project will generate fundamental knowledge on how the peripheral ILC system is regulated by the mobilization and potentially selective trafficking of ILC progenitors into peripheral tissues. The outcomes will greatly enhance our understanding of the maintenance and regulation of peripheral ILCs and will provide novel insights into therapeutic utilization and control of ILC progenitors.

项目概要先天淋巴细胞（ILC）是外周组织的重要组成部分，通过调节组织稳态，免疫和炎症。随着时间的推移，周围 ILC 群体会经历自发和诱导的损耗并应予以补充以维持其正常数量和子集组成。骨髓 (BM) 是为外周组织产生 ILC 祖细胞的主要位点。将 ILC 祖细胞输送到体内的第一步外周组织是来自 BM 的 ILC 祖细胞的动员，这可能需要调节 ILC 祖细胞从 BM 迁移并最终转运到各种外周组织。不幸的是，我们很难理解各种ILC祖细胞是如何从BM和在稳定状态下特征性地分布到各种外周组织以及这些过程是如何进行的炎症条件下发生改变。该项目的总体目标是了解 BM ILC 祖细胞的动员和贩运。在中央 ILC 祖细胞的动员和迁移方面出现了几个重要问题：哪些祖细胞主要从 BM 迁移来产生外周 ILC 子集？他们是否具有多潜能和/或承诺的祖先？触发他们移民的机制和信号是什么？怎么办这些血液循环中的祖细胞进入不同的外周组织？是迁移机制对于每个祖细胞亚群或组织部位来说是通用的还是特异性的？炎症信号如何改变 ILC 祖细胞的动员和迁移模式，以及我们能否控制致病性中的组织 ILC 活性通过利用动员的 BM ILC 祖细胞或针对其动员和迁移来改变条件？我们制定了以下具体目标来调查这些有关动员和动员的问题 ILC 祖细胞的贩运。目标 1. 确定人才保留与迁移的根本机制 BM ILC祖细胞；目标 2. 研究 BM ILC 祖细胞的保留与迁移情况受昼夜节律调节；目标 3. 识别调节保留与保留的炎症信号。 BM ILC 祖细胞的迁移；目标 4. 识别归巢行为和贩运受体迁移的ILC祖细胞。该项目将生成有关外围 ILC 如何该系统通过 ILC 祖细胞的动员和潜在选择性运输到外周血来调节组织。研究结果将极大地增强我们对维护和监管的理解外周 ILC 将为 ILC 的治疗利用和控制提供新的见解祖先。