Lung repair mechanisms mediated by the immune-fibroblast interface

免疫成纤维细胞界面介导的肺修复机制

• 批准号: 10697383
• 负责人: Jarod Zepp
• 金额: $ 44.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697383
• 关键词: Allergens; Cells; Chemicals; Epithelial Cells; Epithelium; Exposure to; Fibroblasts; Foundations; Funding; Future; Genetic; Goals; Homeostasis; Human; Immune; Immunity; Inflammation; Inflammatory Response; Inhalation; Injury; Length; Lung; Lung diseases; Mediating; Mesenchyme; Modeling; Molecular; Mucous body substance; Organ; Organoids; Outcome; Particulate; Pathway interactions; Program Description; Pulmonary alveolar structure; Research; Resolution; Respiration Disorders; Sentinel; Shapes; Signal Transduction; Smooth Muscle; Testing; Tissues; antimicrobial drug; immunological status; in vivo Model; influenza infection; injury and repair; insight; lung injury; lung repair; mouse model; novel; progenitor; programs; respiratory pathogen; response; tissue repair; wound healing

PROJECT SUMMARY The pulmonary mesenchyme, which includes fibroblasts and smooth muscle, provides critical support for resident epithelial progenitors, but how it contributes to lung injury resolution is unclear. As a barrier organ the lung is constantly exposed to inhaled particulates, allergens, and respiratory pathogens. This barrage of exposures is countered by mucous secretions, antimicrobial agents, and sentinel immune cells. In the case of a more severe insult that causes lung damage, the inflammatory response and activation of wound-healing fibroblasts ensues. The research program described here seeks to elucidate how signaling between resident fibroblasts and immune cells controls the length and successful outcome of the lung injury repair response. Further, this research will test a new model proposed for the origins of human lung disease by testing how dysfunctional epithelial cells perpetuate the inflammation-driven fibroblast response. The overarching goal of this program is to determine the molecular pathways utilized by distinct fibroblast subsets and how they converge to shape the immune status of the lung. These questions will be explored by using our unique genetic mouse models for fibroblast lineages and in vivo models of respiratory dysfunction including chemical-induced injury or influenza infection. Moreover, we propose to employ a combination of sequencing analysis and establish novel organoid models to explore the interactions of fibroblast subsets and tissue resident immune cells. Together, our efforts will provide new insights in the mechanisms of lung repair resolution and build a foundation for novel future contributions.

项目总结 肺间充质，包括成纤维细胞和平滑肌，为 居民上皮祖细胞，但它如何有助于肺损伤的解决尚不清楚。作为屏障器官， 肺部经常暴露在可吸入颗粒物、过敏原和呼吸道病原体中。这接二连三的 粘膜分泌物、抗菌剂和哨兵免疫细胞可对抗暴露。在以下情况下 更严重的侮辱，会导致肺损伤、炎症反应和激活伤口愈合 成纤维细胞随之而来。这里描述的研究项目试图阐明居民之间的信号传递 成纤维细胞和免疫细胞控制着肺损伤修复反应的长度和成功的结果。 此外，这项研究将测试提出的关于人类肺部疾病起源的新模型，通过测试 功能失调的上皮细胞使炎症驱动的成纤维细胞反应永久化。这件事的首要目标是 程序是确定不同成纤维细胞亚群利用的分子通路以及它们如何汇聚成 塑造肺部的免疫状态。这些问题将通过使用我们独特的遗传小鼠来探索 成纤维细胞系模型和包括化学性损伤在内的呼吸功能障碍的体内模型 流感感染。此外，我们建议采用测序分析相结合的方法来建立新的 器官模型探索成纤维细胞亚群与组织驻留免疫细胞的相互作用。在一起，我们的 这些努力将为肺修复解决机制提供新的见解，并为新的 未来的贡献。