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.

项目总结 急性和慢性实质性肺部疾病，如急性呼吸窘迫综合征(ARDS)和 特发性肺纤维化(IPF)与严重的发病率和死亡率有关。治疗是有限的， 这在很大程度上是由于我们对疾病发病机制的不完全理解。这些疾病是由于对 肺泡上皮再生效果不佳。根据美国国立卫生研究院的使命，“寻求根本 关于自然…的知识并应用这些知识来增进健康“，我们的目标是确定 肺泡内稳态在损伤过程中被维持、破坏和恢复的机制 生理再生以及这些过程如何在ARDS和IPF的发病机制中出错。 正常肺泡由肺泡2型上皮细胞(AEC2s)和AEC1s组成，形成紧密的屏障， 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 在动态平衡期间维持肺泡静止的机制还知之甚少。在肺损伤期间，血管内皮细胞死亡。严重者 急性损伤导致屏障通透性，导致ARDS；临床恢复需要上皮再生。在……里面 IPF，反复的上皮损伤和受损的再生会导致纤维化。然而，潜在的机制 生理性再生及其在特发性肺纤维化发病机制中是如何受损的尚不完全清楚。 AEC2是负责生理性肺泡再生的主要前体细胞。AEC2增殖，然后 分化为AEC1。我们和其他人已经确定了AEC2增殖的机制。此外，我们是 首次确定了一种新的过渡细胞状态，这种状态是在分化前再生AEC2而瞬时呈现的 变成AEC1。我们还发现，移行细胞在肺纤维化中持续存在，这表明 移行细胞可能是导致纤维化的关键再生缺陷。然而，诱因的机制 AEC2处于过渡状态，在生理过程中过渡细胞分化为AEC1 IPF的再生以及移行细胞持续存在和促进纤维化的机制尚不清楚。 在这里，我们将探讨肺泡细胞-细胞串扰维持动态平衡和促进 生理性再生以及这些机制如何在ARDS和纤维化中出错。我们将使用世系追踪 AEC2特异性可诱导基因敲除联合应用于小鼠体内稳态、损伤、生理学模型 再生和纤维化。培养的人和小鼠血管内皮细胞将被用于解剖机制。建议数 这项工作将填补我们对肺泡动态平衡和生理学和 病理再生和克服开发ARDS新疗法的关键障碍 和IPF。这笔资金还将支持寻求新的调查路线，并致力于适当的 将时间和精力投入到协作、专业服务和指导中。