Defining PRC2 complex epigenomic control in alveolar progenitor cells

项目总结 哺乳动物肺的肺泡区是一个复杂的、结构精确的组织，是初级肺发育所必需的 呼吸系统、气体交换和组织氧合的功能。对肺泡上皮的损伤 在包括急性呼吸窘迫综合征(ARDS)在内的人类肺部疾病中发挥核心作用 流行的、影响很大的临床疾病，影响高达5%的机械通气患者 发达国家。ARDS的死亡率接近40%，ARDS幸存者的恢复是 艰苦，在接下来的5年或更长时间内继续承受多系统残疾的沉重负担 住院治疗。关键是，虽然许多ARDS幸存者恢复了肺功能，但仍有一部分患者出现 持续性肺功能异常，肺部疤痕形成的影像证据，以及肺部症状 甚至在急性呼吸窘迫综合征之后的几年。到目前为止，还没有关于指导ARDS恢复的机制的数据。这些 冠状病毒大流行使挑战变得更加尖锐，它暴露了很大一部分 人类对急性肺损伤的抵抗力。数量庞大的患者面临着急性和非传染性疾病的风险 冠状病毒感染后肺损伤的慢性肺后果，强调明确和紧急 需要新的再生疗法来促进急性肺病的康复。 许多器官的再生是由成体兼性祖细胞驱动的。我们最近发现了一种兼职的 小鼠和人肺中参与病毒损伤后再生的祖细胞，我们称之为肺泡 上皮祖细胞(AEP)。祖细胞小心地控制着它们的染色质，因为它们必须保持更宽的范围 比完全分化的细胞更有潜力，因此祖细胞染色质状态的一个标志是活动区 完全开放和完全封闭状态之间的调节，即所谓的稳定染色质。唯一的初步数据来自 我们的实验室和文献回顾支持这样的观点，即染色质修饰复合体PRC2是一种 AEP祖细胞染色质状态的关键调节因子。在此应用程序中，使用高级 肺有机物和遗传性小鼠损伤模型，我们将确定时间和功能要求 PRC2在肺祖细胞中的作用，定义了PRC2复合体的关键结合伙伴和靶点 维持AEP前体状态，并评估受PRC2复合体活性调节的基因组位点 是AEP介导的肺泡再生所必需的。了解这些基本机制将提供 该框架需要在颗粒水平上了解肺泡再生生物学并开发治疗方法 维持和恢复AT2祖细胞功能以驱动感染和环境修复的策略 压力。

PROJECT SUMMARY The alveolar region of the mammalian lung is a complex, precisely structured tissue required for the primary functions of the respiratory system, gas exchange and tissue oxygenation. Damage to the alveolar epithelium plays a central role in human lung diseases including Acute Respiratory Distress Syndrome (ARDS), a prevalent, high impact clinical disorder that affects up to 5% of mechanically ventilated patients in the developed world. The mortality rate of ARDS approaches 40%, and the recovery for ARDS survivors is arduous, with a substantial burden of multi-system disability continuing 5 or more years following hospitalization. Critically, while many ARDS survivors recover lung function, a subset of patients develops persistently abnormal pulmonary function, imaging evidence of pulmonary scarring, and pulmonary symptoms even years after ARDS. To date, no data exists regarding the mechanisms that guide ARDS recovery. These challenges have been made more acute by the coronavirus pandemic, which has exposed a large proportion of the human population to acute lung injury. An enormous population of patients is at risk of both acute and chronic lung consequences of lung injury following coronavirus infection, emphasizing the clear and urgent need for new regenerative therapies to promote recovery from acute lung disease. Regeneration in many organs is driven by adult facultative progenitor cells. We recently discovered a facultative progenitor cell in the mouse and human lung which participates in regeneration after viral injury we call alveolar epithelial progenitors (AEPs). Progenitor cells control their chromatin carefully, as they must maintain more broad potential than fully differentiated cells, and so a hallmark of progenitor chromatin state is regions of active regulation between fully open and fully closed states, so called poised chromatin. Unique preliminary data from our laboratory and review of the literature support the idea that the chromatin modifying complex PRC2 is a critical regulator of the progenitor chromatin state of AEPs. In this application, using a combination of advanced lung organoids and genetic mouse injury models, we will identify the temporal and functional requirements for PRC2 function in lung progenitors, define the key binding partners and targets of the PRC2 complex in maintenance of AEP progenitor state, and evaluate the genomic loci regulated by PRC2 complex activity necessary for AEP-mediated alveolar regeneration. Understanding these fundamental mechanisms will provide the framework needed to understand alveolar regenerative biology at a granular level and develop therapeutic strategies to maintain and restore AT2 progenitor function to drive repair following infection and environmental stress.