Beyond the Barrier: Alveolar Epithelial Cell Biology in Health and Disease

最初被认为是阻止液体被动渗入肺空气的简单屏障，对气体至关重要 现在，肺泡上皮被认为是肺泡动态平衡的关键调节因素。此外， 肺泡上皮细胞的改变是许多影响呼吸道疾病的发病机制的核心。 健康，包括特发性肺纤维化(IPF)和肺气肿，因此了解 负责其正常维护和损伤后修复的机制。我的研究项目是 主题集中在肺泡上皮细胞(AEC)的可塑性/重新编程，总体目标是 鉴定AEC功能和表型的分子基础以阐明导致AEC功能和表型的机制 异常修复并制定策略以改善损伤后的结果，与 NHLBI。到目前为止，我们的工作为AEC生物学中的新范式做出了贡献，包括展示了 肺泡上皮I型(AT1)细胞在肺泡动态平衡、AEC可塑性中的积极作用 肺纤维化中的肺泡上皮，发现紧密连接(TJ)在肺调节中的新作用 干细胞/祖细胞的动态平衡，以及调控AEC分化的关键途径的阐明。在基础上建设 在这项工作中，我们将重点推进1)正常AEC监管的补充领域 表型/分化，2)AEC在肺纤维化中的作用，3)内源性肺干/祖细胞的调节 通过与TJ的相互作用来协调细胞动态平衡，以解决我们对 疾病中正常的AEC祖细胞潜能/分化和破坏。成功将通过以下方式确保) 在AEC分化、肺发育、 表观遗传学/生物信息学和再生医学以及b)使用创新模式(例如，诱导 取自正常和IPF患者的多能细胞(IPSC)，以研究AEC在健康和疾病中的分化。 全基因组和高通量技术的应用将提供潜在的变革性 对先前未探索的细胞特异性表观遗传(尤其是组蛋白)修饰调控正常的洞察力 正常AEC和IPF AEC分化异常。关于肺干/祖细胞调控的新见解 通过细胞内转导来自TJ的信号的功能有可能被利用来增强肺 受伤后的再生。广泛应用于肺病研究界的成果包括改进 AT1细胞分离方法、新的AT1细胞标记/Cre系和全基因组数据集 共享资源。我们的综合团队方法使用原代(包括人类)AEC、球体培养和 IPSC，连同全基因组转录/表观基因组分析和疾病建模，以解决 与AEC维护和维修相关的关键问题具有显著的翻译潜力。虽然 该计划的一些方面具有潜在的高风险，这些正是提供新研究的类型 创新研究机会，并将从该奖项提供的长期支持中获益最多。

Originally regarded as a simple barrier against passive leakage of fluid into lung airspaces critical for gas exchange, the alveolar epithelium is now viewed as a key regulator of alveolar homeostasis. Furthermore, alterations in alveolar epithelium are central to the pathogenesis of a number of diseases impacting respiratory health including idiopathic pulmonary fibrosis (IPF) and emphysema, making it important to understand mechanisms responsible for its normal maintenance and repair following injury. My research program is thematically focused on alveolar epithelial cell (AEC) plasticity/‘reprogramming’, with the overall goal of characterizing the molecular basis of AEC function and phenotype in order to elucidate mechanisms leading to aberrant repair and develop strategies for improving outcome following injury, consistent with the mission of NHLBI. Our work to date has contributed to new paradigms in AEC biology, including demonstration of an active role for alveolar epithelial type I (AT1) cells in alveolar homeostasis, AEC plasticity, a central role for alveolar epithelium in pulmonary fibrosis, discovery of a novel role of tight junctions (TJ) in regulation of lung stem/progenitor cell homeostasis, and elucidation of key pathways regulating AEC differentiation. Building on this work, we will focus going forward on complementary areas of 1) regulation of normal AEC phenotype/differentiation, 2) role of AEC in lung fibrosis and 3) regulation of endogenous lung stem/progenitor cell homeostasis coordinated by interactions with TJ, in order to address key gaps in our understanding of normal AEC progenitor potential/differentiation and disruption in disease. Success will be ensured by a) synergistic interactions among a strong team with expertise in AEC differentiation, lung development, epigenetics/bioinformatics and regenerative medicine and b) use of innovative models (e.g., induced pluripotent cells (iPSC) from normal and IPF patients) to investigate AEC differentiation in health and disease. Application of genome-wide genomic and high-throughput technologies will provide potentially transformative insights into previously unexplored cell-specific epigenetic (especially histone) modifications regulating normal and aberrant differentiation of normal and IPF AEC. Novel insights regarding regulation of lung stem/progenitor function by intracellular transduction of signals from TJ have the potential to be harnessed to augment lung regeneration after injury. Deliverables with broad application to the lung research community include improved methods for AT1 cell isolation, novel AT1 cell markers/Cre lines, and genome-wide datasets to be deposited as a shared resource. Our integrated team approach using primary (including human) AEC, spheroid cultures and iPSC, together with genome-wide transcriptomic/epigenomic analyses and disease modelling, to address critical questions related to AEC maintenance and repair has significant translational potential. Although aspects of the program are potentially high-risk, these are precisely the types of studies that provide new innovative research opportunities and will benefit most from the long-term support provided by this award.