Mechanisms of Alveolar Homeostasis, Injury, Regeneration, and Fibrosis

项目摘要 急性和慢性实质性肺疾病，如急性呼吸窘迫综合征（ARDS）和 特发性肺纤维化（IPF）与显著发病率和死亡率相关。治疗方法有限， 这主要是由于我们对疾病发病机理的不完全理解。这些疾病是由于对心脏的损伤引起的。 肺泡上皮细胞再生无效。根据NIH的使命，“寻求基本的 了解生命系统的性质，并应用这些知识来增强健康”，我们的目标是确定 肺泡内稳态的维持机制，在损伤期间被破坏，并在损伤后恢复。 生理再生以及这些过程在ARDS和IPF发病机制中如何出错。 正常肺泡由肺泡2型上皮细胞（AEC 2）和AEC 1组成，它们形成紧密的屏障， 与静止的成纤维细胞和肺泡巨噬细胞。细胞间串扰的分子机制， 在体内平衡过程中维持肺泡静止还知之甚少。在肺损伤期间，AEC死亡。严重 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 IPF，重复性上皮损伤伴再生受损引起纤维化。然而， 生理再生及其在IPF发病机制中如何受损尚不完全清楚。 AEC 2是负责生理性肺泡再生的主要祖细胞。AEC 2增殖，然后 区分为AEC 1。我们和其他人已经确定了AEC 2增殖的机制。此外，我们 第一个识别出一种新的过渡细胞状态，这种状态是在分化前通过再生AEC 2暂时呈现的。 AEC1我们还发现在肺纤维化中移行细胞持续存在，这表明 移行细胞可能是导致纤维化的关键再生缺陷。然而，诱导的机制 在生理过程中，AEC 2呈现过渡状态，过渡细胞分化为AEC 1 尚不清楚移行细胞通过何种途径存活并促进IPF中的纤维化。 在这里，我们将探讨肺泡细胞间串扰的机制，维持体内平衡，并促进 生理再生以及这些机制在ARDS和纤维化中是如何出错的。我们将使用血统追踪 与AEC 2特异性诱导型基因敲除结合，在稳态、损伤、生理性 再生和纤维化。培养的人和鼠AEC将用于解剖机制。拟议 这项工作将填补我们对肺泡内稳态和生理及 病理再生和克服关键障碍，发展新的治疗方法，为ARDS IPF。这笔资金还将支持寻求新的调查路线和适当的奉献精神。 时间和精力投入到合作、专业服务和指导中。

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.