Defining PRC2 complex epigenomic control in alveolar progenitor cells

定义肺泡祖细胞中 PRC2 复杂的表观基因组控制

• 批准号: 10560727
• 负责人: William John Zacharias
• 金额: $ 55.61万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560727
• 关键词: ATAC-seq; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adult; Affect; Alveolar; Animals; Attention; Automobile Driving; Binding; Biology; Cell Differentiation process; Cells; ChIP-seq; Chemicals; Chromatin; Chromatin Remodeling Factor; Chronic; Clinical; Co-Immunoprecipitations; Complex; Computer Analysis; Coronavirus Infections; Cre driver; Data; Deposition; Disease; Drug Targeting; Ensure; Epigenetic Process; Epithelial Cells; Future; Gases; Genetic; Genetic Transcription; Genome; Genomics; Grant; Homeostasis; Hospitalization; Human; Image; In Vitro; Infection; Influenza; Injury; Laboratories; Literature; Longevity; Lung; Lung diseases; Maintenance; Mechanical ventilation; Mediating; Modeling; Molecular Conformation; Mus; Natural regeneration; Organ; Organoids; Patients; Pharmaceutical Preparations; Phenotype; Play; Pneumonia; Population; Process; Proliferating; Proteomics; Publishing; RNA; Recovery; Regulation; Respiratory System; Respiratory physiology; Review Literature; Risk; Role; SARS-CoV-2 infection; Specific qualifier value; Specificity; Stable Populations; Stress; Structure; Survivors; System; Testing; Therapeutic; Time; Tissues; Ventilator; Viral; Work; alveolar epithelium; combinatorial; constitutive expression; coronavirus pandemic; disability; epigenomics; epithelium regeneration; exhaustion; fibrotic lung; gene repression; genomic locus; healing; improved; in vivo; influenza infection; insight; lung injury; lung regeneration; mortality; novel; patient population; patient subsets; premature; prevent; progenitor; pulmonary function; pulmonary symptom; regeneration potential; regenerative; regenerative biology; regenerative therapy; repaired; self-renewal; stem cells; therapeutic development; tissue oxygenation

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.

项目摘要 哺乳动物肺的肺泡区域是一种复杂的、精确结构的组织，其是肺的主要功能所需的。 呼吸系统、气体交换和组织氧合的功能。肺泡上皮损伤 在包括急性呼吸窘迫综合征（ARDS）在内的人类肺部疾病中起着核心作用， 流行的、高影响的临床疾病，影响了美国5%的机械通气患者， 发达世界。急性呼吸窘迫综合征（ARDS）的死亡率接近40%，存活者的康复率为100%。 艰苦，多系统残疾的巨大负担持续5年或更长时间， 住院重要的是，虽然许多ARDS幸存者恢复了肺功能，但仍有一部分患者发展为 肺功能持续异常、肺部瘢痕形成的影像学证据和肺部症状 即使是在ARDS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严峻， 急性肺损伤的发病率大量的患者处于急性和慢性疾病的风险中。 冠状病毒感染后肺损伤的慢性肺后果，强调明确和紧迫的 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 小鼠和人肺中参与病毒损伤后再生的祖细胞，我们称为肺泡 上皮祖细胞（AEPs）。祖细胞小心地控制它们的染色质，因为它们必须保持更宽的染色质。 因此，祖细胞染色质状态的一个标志是活性区域， 在完全开放和完全关闭状态之间的调节，所谓的平衡染色质。独特的初步数据， 我们的实验室和文献综述支持染色质修饰复合物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 肺类器官和遗传小鼠损伤模型，我们将确定时间和功能的要求， PRC2在肺祖细胞中的功能，定义了肺祖细胞中PRC2复合物的关键结合伴侣和靶标。 维持AEP祖细胞状态，并评估PRC2复合物活性调节的基因组位点 AEP介导的肺泡再生所必需的。了解这些基本机制将提供 在颗粒水平上理解肺泡再生生物学和开发治疗方法所需的框架 维持和恢复AT2祖细胞功能以驱动感染和环境损伤后修复的策略 应力