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

超越障碍：健康和疾病中的肺泡上皮细胞生物学

• 批准号: 10671502
• 负责人: Zea Borok
• 金额: $ 94.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671502
• 关键词: Abnormal Cell; Address; Alveolar Cell; Area; Award; Bioinformatics; Biology; Cell Differentiation process; Cell Maintenance; Cell Separation; Cell physiology; Cells; Cellular biology; Chronic lung disease; Communities; Data Set; Deposition; Development; Disease; Disease model; Ensure; Epigenetic Process; Epithelial Cells; Extravasation; Fibrosis; Gases; Genomics; Goals; Health; Histones; Human; Injury; Liquid substance; Lung; Maintenance; Methods; Mission; Modeling; Modification; Molecular; National Heart, Lung, and Blood Institute; Pathogenesis; Pathway interactions; Patients; Phenotype; Pulmonary Emphysema; Pulmonary Fibrosis; Regenerative Medicine; Regulation; Research; Research Design; Resource Sharing; Role; Signal Transduction; Surface; Therapeutic; Tight Junctions; Work; alveolar epithelium; alveolar homeostasis; epigenomics; epithelial stem cell; genome-wide; high risk; high throughput technology; idiopathic pulmonary fibrosis; improved; improved outcome; induced pluripotent stem cell; innovation; insight; lung development; lung injury; lung regeneration; novel; progenitor; programs; repaired; respiratory health; stem; stem cell homeostasis; success; transcriptomics; translational potential

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.

最初被认为是防止液体被动泄漏到对气体至关重要的肺空间的简单屏障 由于肺泡上皮细胞是肺泡内环境稳定的关键调节因子，因此肺泡上皮细胞是肺泡内环境稳定的关键调节因子。此外，委员会认为， 肺泡上皮细胞的改变是许多影响呼吸系统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 在受伤后负责其正常维护和修复的机制。我的研究项目是 主题集中在肺泡上皮细胞（AEC）可塑性/“重编程”，总体目标是 表征AEC功能和表型的分子基础，以阐明导致 异常修复，并制定策略，以改善受伤后的结果，符合使命， NHLBI。迄今为止，我们的工作为AEC生物学的新范式做出了贡献，包括展示了 肺泡上皮I型（AT 1）细胞在肺泡内稳态、AEC可塑性中的积极作用， 肺泡上皮细胞在肺纤维化中的作用，紧密连接（TJ）在肺纤维化调节中的新作用的发现 干/祖细胞稳态，并阐明调控AEC分化的关键途径。基础上 在这项工作中，我们将把重点放在以下补充领域：1）正常AEC的监管 表型/分化，2）AEC在肺纤维化中的作用和3）内源性肺干/祖细胞的调节 通过与TJ的相互作用协调细胞内稳态，以解决我们理解的关键空白， 疾病中正常AEC祖细胞潜能/分化和破坏。成功的保证是：a） 在AEC分化，肺发育， 表观遗传学/生物信息学和再生医学和B）使用创新模型（例如，诱导 来自正常和IPF患者的多能细胞（iPSC）来研究健康和疾病中的AEC分化。 全基因组基因组和高通量技术的应用将提供潜在的变革性 深入了解以前未探索的细胞特异性表观遗传（尤其是组蛋白）修饰调节正常 以及正常和IPF AEC的异常分化。关于肺干/祖细胞调节的新见解 通过来自TJ的信号的细胞内转导的功能具有被利用以增加肺功能的潜力。 损伤后的再生广泛应用于肺研究界的可接受物包括改进的 用于AT 1细胞分离的方法、新的AT 1细胞标志物/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）AEC，球状体培养物和 iPSC与全基因组转录组/表观基因组分析和疾病建模一起， 与AEC维护和维修相关的关键问题具有重大的转化潜力。虽然 该计划的各个方面都是潜在的高风险，这些正是提供新的研究类型。 创新的研究机会，并将受益于该奖项提供的长期支持。