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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：
10766537
负责人：
CHANG H KIM
金额：
$ 14.84万
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：
2023-02-09 至 2023-07-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY ILCs play essential roles in 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. The first step to deliver ILC progenitors into peripheral tissues is the mobilization of ILC progenitors from the central hematopoietic tissue, bone marrow (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 key questions arise in terms of the mobilization and migration of central ILC progenitors: Which progenitors dominantly emigrate from BM to generate peripheral ILC subsets in steady state? 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 mechanism that mobilizes central ILC progenitors in steady state; Aim 2. Identify the mechanism by which central ILC progenitors are mobilized in inflammatory conditions; Aim 3. Identify potentially diverse mechanisms for the entrance of mobilized ILC progenitors into distinct peripheral tissues. The project will generate fundamental knowledge on how the peripheral ILC system is maintained and 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 ILC 通过调节组织稳态、免疫和炎症在外周组织中发挥重要作用。随着时间的推移，周围 ILC 群体会经历自发和诱导的消耗，应予以补充保持其正常数量和子集组成。将 ILC 祖细胞输送到外周血的第一步组织是来自中央造血组织、骨髓 (BM) 的 ILC 祖细胞的动员，并且这个大概需要 ILC 祖细胞从 BM 中受管制地移出并最终贩运到各种周围组织。不幸的是，我们很难理解不同的 ILC 祖细胞是如何变化的。从 BM 动员并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在炎症条件下如何改变。本次活动的总体目标是该项目旨在了解 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关键问题：祖细胞主要从 BM 迁移以产生稳定状态下的外周 ILC 子集？他们是多潜在的和/或承诺的祖先？触发他们移民的机制和信号是什么？血液循环中的这些祖细胞如何进入不同的外周组织？是否迁移对于每个祖细胞亚群或组织部位来说，机制是通用的还是特定的？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. 确定动员中央 ILC 祖细胞的机制稳定状态;目标 2. 确定中央 ILC 祖细胞在炎症状况；目标 3. 确定动员人员进入的潜在多样化机制 ILC 祖细胞分化为不同的外周组织。该项目将产生关于如何外围 ILC 系统通过动员和潜在选择性贩运来维持和调节 ILC祖细胞进入外周组织。这些成果将极大地加深我们对外周 ILC 的维持和调节，将为治疗提供新的见解 ILC祖细胞的利用和控制。