Lung leukocytes promote alveolar epithelial regeneration after severe injury

肺白细胞促进严重损伤后肺泡上皮再生

• 批准号: 10666350
• 负责人: Nicholas Arpaia
• 金额: $ 62.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666350
• 关键词: Ablation; Acute; Acute Lung Injury; Alveolar; Amphiregulin; Anatomy; Binding; Cells; Chronic; Cues; Development; Disease model; Distal; Environment; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Exhibits; Functional disorder; Future; Gene Expression; Genetic; Goals; Growth Factor; Homeostasis; Image; Immune; Immune response; Immune signaling; Immune system; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Kinetics; Leucocytic infiltrate; Leukocytes; Ligands; Link; Lung; Lung diseases; Lymphocyte; Mediating; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Modeling; Molecular; Mus; Natural regeneration; Organ; Outcome; Pathogenicity; Pattern; Phase; Physiological; Play; Population; Process; Production; Proliferating; Regenerative Medicine; Regulation; Regulatory T-Lymphocyte; Report (document); Resolution; Role; Severities; Signal Induction; Signal Transduction; Source; Spatial Distribution; Sterility; Stimulus; Structure of parenchyma of lung; Supporting Cell; T-Lymphocyte; Testing; Tissues; Tumor Immunity; Viral Respiratory Tract Infection; Wound models; airway regeneration; alveolar epithelium; cell type; epithelial stem cell; epithelium regeneration; immunological diversity; in vivo; influenza infection; influenzavirus; interdisciplinary approach; lung injury; lung preservation; lung regeneration; lung repair; organ growth; pathogen; progenitor; programs; protective factors; pulmonary function; recruit; regenerative; repaired; response; restoration; severe injury; skin wound; stem; stem cell population; stem cells; therapeutic candidate; therapeutic development; tissue injury; tissue regeneration; tissue repair; tool

PROJECT SUMMARY/ABSTRACT It has become increasingly appreciated that lymphocytes within non-lymphoid tissues exhibit unique effector programs that extend beyond their roles in anti-pathogen and anti-tumor immunity. Such non-immune functions, including the regulation of metabolic homeostasis and tissue repair, highlight the diversity of immunological signals that can be elaborated in a tissue-specific manner to modify physiological and developmental parameters within a given niche. To achieve these diverse regulatory roles, tissue-localized leukocytes interact with specialized non-lymphoid cells that define the organ’s function, triggering niche-specific effector programs in response to perturbations within the tissue microenvironment. In support of this mechanism, a recently described population of lung regulatory T (Treg) cells were shown to play a pronounced tissue-protective role during the early stages of acute lung injury caused by influenza virus infection in mice. Through their production of the epidermal growth factor receptor (EGFR) ligand, amphiregulin, these Treg cells support epithelial barrier regeneration and preserve lung function. Although these findings uncovered an important and previously unknown role for Treg cell–derived amphiregulin, the mechanistic details of how amphiregulin influences lung repair remained undetermined. Preliminary studies indicate that in response to lung injury caused by other damaging stimuli, infiltrating leukocyte populations other than regulatory T cells produce amphiregulin. Further inspection has suggested that amphiregulin-producing leukocytes may guide alveolar epithelial regeneration by interacting with specific lung mesenchymal and epithelial stem/progenitor cell populations that orchestrate discrete steps of the repair process. To this end, the major goals of this proposal are to 1) characterize interactions between amphiregulin-producing lung leukocytes and resident mesenchymal and epithelial stem/progenitor cells, 2) identify the molecular basis of these interactions and define their relative significance for restoring normal lung function, and 3) determine how these cellular interactions are influenced by the severity or type of damaging stimuli. Successful completion of this project will broaden our understanding of the role of tissue-specific immune responses in directing tissue regeneration and support the development of future strategies that seek to stimulate these processes to treat lung disease and restore normal organ homeostasis.

项目概要/摘要 人们越来越认识到非淋巴组织内的淋巴细胞表现出独特的效应 超出其抗病原体和抗肿瘤免疫作用的程序。这种非免疫功能， 包括代谢稳态的调节和组织修复，突出免疫学的多样性 可以以组织特异性方式详细说明以修改生理和发育参数的信号 在给定的利基内。为了实现这些不同的调节作用，组织局部白细胞与 定义器官功能的专门非淋巴细胞，触发特定环境的效应程序 对组织微环境中的扰动的反应。为了支持这一机制，最近描述了 肺调节性 T (Treg) 细胞群被证明在 小鼠流感病毒感染引起的急性肺损伤的早期阶段。通过他们的生产 表皮生长因子受体 (EGFR) 配体、双调蛋白，这些 Treg 细胞支持上皮屏障 再生并保护肺功能。尽管这些发现揭示了先前的一个重要的 Treg 细胞衍生的双调蛋白的作用未知，双调蛋白如何影响肺的机制细节 修复尚未确定。初步研究表明，为了应对其他原因引起的肺损伤 破坏性刺激、除了调节性 T 细胞之外的浸润性白细胞群会产生双调蛋白。更远 检查表明，产生双调蛋白的白细胞可能通过以下方式指导肺泡上皮再生： 与特定的肺间充质和上皮干/祖细胞群相互作用，协调 修复过程的离散步骤。为此，本提案的主要目标是 1) 描述 产生双调蛋白的肺白细胞与常驻间充质和上皮细胞之间的相互作用 干/祖细胞，2) 确定这些相互作用的分子基础并定义它们的相对重要性 用于恢复正常的肺功能，以及 3) 确定严重程度如何影响这些细胞相互作用 或破坏性刺激的类型。该项目的成功完成将加深我们对 组织特异性免疫反应指导组织再生并支持未来的发展 寻求刺激这些过程来治疗肺部疾病和恢复正常器官稳态的策略。