Mechanisms of Alveolar Homeostasis, Injury, Regeneration, and Fibrosis

肺泡稳态、损伤、再生和纤维化的机制

• 批准号: 10348551
• 负责人: Rachel Lynne Zemans
• 金额: $ 91.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2029-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348551
• 关键词: Acute; Acute Respiratory Distress Syndrome; Alveolar; Alveolar Cell; Alveolar Macrophages; Alveolus; Automobile Driving; Cells; Chronic; Chronic lung disease; Clinical; Collaborations; Dedications; Defect; Development; Disease; Epithelial Cells; Fibroblasts; Fibrosis; Funding; Health; Homeostasis; Human; Impairment; Injury; Investigation; Knowledge; Lung diseases; Mentorship; Mission; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Nature; Organism; Pathogenesis; Pathologic; Permeability; Physiological; Process; Proliferating; Pulmonary Fibrosis; Recovery; Services; Time; Transitional Cell; United States National Institutes of Health; Work; alveolar epithelium; alveolar homeostasis; effective therapy; epithelial injury; epithelium regeneration; idiopathic pulmonary fibrosis; knockout gene; lung injury; mortality; mouse model; novel; novel therapeutics; progenitor; regenerative

PROJECT SUMMARY Acute and chronic parenchymal lung diseases, such as the acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF), are associated with significant morbidity and mortality. Therapies are limited, largely due to our incomplete understanding of disease pathogenesis. These diseases arise from injury to the alveolar epithelium with ineffectual regeneration. In accordance with the NIH mission to “seek fundamental knowledge about the nature…of living systems and apply that knowledge to enhance health”, we aim to identify mechanisms by which alveolar homeostasis is maintained, disrupted during injury, and restored during physiologic regeneration and how these processes go awry in the pathogenesis of ARDS and IPF. The normal alveolus consists of alveolar type 2 epithelial cells (AEC2s) and AEC1s, which form a tight barrier, with quiescent fibroblasts and alveolar macrophages. The molecular mechanisms of cell-cell crosstalk that maintain alveolar quiescence during homeostasis are poorly understood. During lung injury, AECs die. Severe acute injury results in barrier permeability, leading to ARDS; clinical recovery requires epithelial regeneration. In IPF, repetitive epithelial injury with impaired regeneration begets fibrosis. However, the mechanisms underlying physiologic regeneration and how it is impaired in the pathogenesis of IPF are incompletely understood. AEC2s are the primary progenitor responsible for physiologic alveolar regeneration. AEC2s proliferate, then differentiate into AEC1s. We and others have identified mechanisms of AEC2 proliferation. Moreover, we were the first to identify a novel transitional cell state transiently assumed by regenerating AEC2s before differentiating into AEC1s. We also found that transitional cells persist in pulmonary fibrosis, suggesting that persistence of transitional cells may be the critical regenerative defect driving fibrosis. However, the mechanisms that induce AEC2s to assume the transitional state and transitional cells to differentiate into AEC1s during physiologic regeneration and by which transitional cells persist and promote fibrosis in IPF are unknown. Here, we will explore the mechanisms of alveolar cell-cell crosstalk that maintain homeostasis and promote physiologic regeneration and how these mechanisms go awry in ARDS and fibrosis. We will use lineage tracing combined with AEC2-specific inducible gene knockout in mouse models of homeostasis, injury, physiologic regeneration, and fibrosis. Cultured human and murine AECs will be used to dissect mechanism. The proposed work will fill fundamental gaps in our understanding of alveolar homeostasis and physiologic and pathologic regeneration and overcome critical barriers to the development of novel therapies for ARDS and IPF. The funding will also support the pursuit of new lines of investigation and the dedication of appropriate time and energy into collaborations, professional service, and mentorship.

项目摘要 急性和慢性副肺肺疾病，例如急性呼吸窘迫综合征（ARDS）和 特发性肺纤维化（IPF）与明显的发病率和死亡率有关。疗法有限， 很大程度上是由于我们对疾病发病机理的不完全理解。这些疾病是由伤害引起的 牙槽上皮，无效再生。根据NIH的使命，要“参见基本 关于生活系统的性质的知识，并将这些知识应用于增强健康”，我们旨在确定 维持肺泡体内平衡的机制，在受伤期间破坏并在期间恢复 生理再生以及这些过程在ARDS和IPF的发病机理中如何出现。 正常肺泡由牙槽2型上皮细胞（AEC2S）和AEC1s组成，它们形成紧密的屏障， 具有静止的成纤维细胞和肺泡巨噬细胞。细胞细胞串扰的分子机制 在体内平衡期间保持肺泡静止是很少的。在肺部受伤期间，AEC死亡。严重 急性损伤导致屏障渗透率，导致ARDS；临床恢复需要上皮再生。在 IPF，重复的上皮损伤，再生受损会受到纤维化的影响。但是，基础机制 生理再生及其在IPF发病机理中的损害如何受损。 AEC2是负责生理肺泡再生的主要祖细胞。然后，AEC2扩散 分为AEC1。我们和其他人已经确定了AEC2增殖的机制。而且，我们是 第一个通过在区分之前通过再生AEC2来识别新型过渡细胞状态的新型过渡细胞状态 进入AEC1。我们还发现过渡细胞持续存在于肺纤维化中，这表明 过渡细胞可能是驱动纤维化的关键再生缺陷。但是，影响的机制 AEC2在生理过程中假设过渡状态和过渡细胞分化为AEC1 再生以及过渡细胞在IPF中持续存在并促进纤维化是未知的。 在这里，我们将探讨维持体内平衡并促进的肺泡细胞串扰的机制 生理再生以及这些机制如何在ARD和纤维化中出现问题。我们将使用谱系跟踪 与AEC2特异性诱导型基因敲除在小鼠稳态，损伤，生理学的模型中结合 再生和纤维化。培养的人和鼠类AEC将用于剖析机制。提议 工作将填补我们对肺泡稳态和生理学和生理和生理和生理的基本空白 病理再生并克服了新型ARDS开发的关键障碍 和IPF。资金还将支持追求新的投资线和适当的奉献 时间和精力进行合作，专业服务和心态。