Understanding the impact of group 2 innate lymphoid cells on airway epithelial regeneration and repair

了解第 2 组先天淋巴细胞对气道上皮再生和修复的影响

• 批准号: 10683709
• 负责人: Alexandra Ysasi
• 金额: $ 0.45万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683709
• 关键词: Acute; Address; Airway Disease; Alveolar; Animals; Asthma; Attention; Basal Cell; Biology; Cell Count; Cell Differentiation process; Cell Proliferation; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Complex; Data; Diphtheria Toxin; Distal; Epithelial Cells; Epithelium; Event; Functional disorder; Future; Gene Deletion; Genetic Transcription; Growth; Homeostasis; Human; Human Biology; Hyperactivity; Immune; Inflammatory Response; Injury; Interleukin Activation; Interleukin Receptor; Interleukins; Knowledge; Lung; Lymphoid Cell; Mediating; Modeling; Mus; Natural regeneration; Pathogenesis; Peptide Initiation Factors; Phosphorylation; Population; Process; Production; Proliferating; Regulation; Research; Role; Series; Signal Transduction; Sterility; Structure; Structure of parenchyma of lung; Testing; Tissues; Trachea; Tracheal Epithelium; Transgenic Mice; Transgenic Organisms; airway epithelium; airway inflammation; airway regeneration; airway repair; cytokine; epithelial injury; epithelial repair; epithelium regeneration; experimental study; genetic manipulation; immune activation; immune modulating agents; immunoregulation; injured airway; mouse model; novel; progenitor; receptor binding; repaired; response; response to injury; single-cell RNA sequencing; stem cells; targeted treatment; tissue repair; transgene expression; treatment strategy

ABSTRACT Epithelial dysfunction is critical in the pathogenesis of human conducting airway diseases such as COPD and asthma. Immune cells are known to influence epithelial composition and function in a variety of tissues. Group 2 innate lymphoid cells (ILC2s) are immune cells that have recently been shown to promote epithelial repair in the lung parenchyma in several murine injury models by promoting growth of distal facultative epithelial progenitors. While hyperactive ILC2s in the airway are known to contribute to chronic airway inflammation, the role of ILC2s in regulating epithelial regeneration and repair in the airway is unknown. To address this gap in knowledge, we will study ILC2s in the context of epithelial injury in the mouse trachea, which models the biology of the human conducting airways. Normal epithelial repair in the trachea occurs via expansion and differentiation of basal stem cells that give rise to all airway epithelial lineages. We will test the hypothesis that ILC2s contribute to airway epithelial repair by regulating proliferation and differentiation of basal cells. We hypothesize that the epithelial alarmin interleukin-33 (IL-33) is a critical signaling factor that initiates immune cell activation during airway regeneration and repair. Aim 1 will characterize the ILC2 response to airway injury and determine whether ILC2s are required for effective epithelial repair. Aim 2 will examine the IL-33/ST2 signaling axis as a potential mechanism by which immune cells respond to injury and promote repair. Targeted transgenic deletion and manipulation of ILC2s will provide cell-specific evidence of ILC2 involvement in airway epithelial regeneration. Interrogation of intracellular phosphorylation events and cytokine production will further elucidate the signaling mechanisms that promote epithelial remodeling and regeneration. Understanding the mechanisms of ILC2 activation and regulation of airway epithelial function will contribute to our understanding of human airway biology and provide potential targets for the therapeutic immunomodulation of human airway diseases.

摘要 上皮功能障碍在人类传导性呼吸道疾病的发病机制中至关重要，如COPD和 哮喘。已知免疫细胞影响多种组织中的上皮成分和功能。集团化 先天淋巴样细胞(ILC2s)是一种免疫细胞，最近被证明能促进上皮修复。 促进远端兼性上皮生长对几种小鼠肺损伤模型肺实质的影响 祖先。虽然已知呼吸道中过度活跃的ILC2有助于慢性呼吸道炎症，但 ILC2s在调节呼吸道上皮再生和修复中的作用尚不清楚。为了弥补这一差距， 知识，我们将在小鼠气管上皮损伤的背景下研究ILC2，这将模拟 人体导气管的生物学。气管内正常的上皮修复是通过扩张和 分化的基础干细胞，从而形成所有的呼吸道上皮细胞系。我们将检验这一假设 ILC2s通过调节基底细胞的增殖和分化促进呼吸道上皮修复。我们 假设上皮细胞警报蛋白白介素33(IL-33)是启动免疫的关键信号因子 细胞在呼吸道再生和修复过程中的激活。目标1将描述ILC2对呼吸道损伤的反应 并确定有效的上皮修复是否需要ILC2。AIM 2将检查IL-33/ST2 信号轴是免疫细胞对损伤做出反应并促进修复的一种潜在机制。目标明确 ILC2的转基因缺失和操作将提供ILC2参与呼吸道的细胞特异性证据 上皮再生。对细胞内磷酸化事件和细胞因子产生的询问将进一步 阐明促进上皮重塑和再生的信号机制。了解 ILC2激活和调节呼吸道上皮功能的机制将有助于我们理解 并为人类呼吸道的治疗性免疫调节提供潜在靶点 疾病。