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

基本信息

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
项目类别：
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

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

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项目摘要

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主要的，精确的结构组织呼吸系统，气体交换和组织氧合的功能。肺泡上皮的损害在包括急性呼吸窘迫综合征（ARDS）的人类肺部疾病中起着核心作用流行，高影响临床疾病，在该疾病中影响多达5％的机械通风患者发达世界。 ARDS的死亡率接近40％，ARDS幸存者的回收率为艰苦，在5年以上的5年或更长时间以前，多系统残疾负担很大住院。至关重要的是，尽管许多ARDS幸存者恢复了肺功能，但一部分患者发展持续异常的肺功能，肺疤痕的成像证据和肺症状甚至在ARDS之后的几年。迄今为止，尚无有关指导恢复的机制的数据。这些冠状病毒大流行使挑战更加敏锐，这已经暴露了很大的比例人口急性肺损伤。大量患者有急性和冠状病毒感染后肺损伤的慢性肺后果，强调清晰而紧急需要新的再生疗法来促进急性肺部疾病的康复。许多器官的再生是由成人辅助祖细胞驱动的。我们最近发现了一个教师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（AEP）。祖细胞仔细控制其染色质，因为它们必须保持更宽潜力比完全分化的细胞，因此祖细胞染色质状态的标志是活性的区域完全开放和完全封闭的状态之间的调节，所谓的染色质。来自独特的初步数据我们的实验室和文献综述支持以下观点，即修饰复合物PRC2是一个 AEPS祖细胞染色质状态的关键调节剂。在此应用程序中，结合了高级肺节和遗传小鼠损伤模型，我们将确定的时间和功能要求 PRC2在肺祖细胞中的功能，定义PRC2复合物的关键结合伙伴和目标维持AEP祖细胞状态，并评估由PRC2复合活动调节的基因组基因座对于AEP介导的肺泡再生所需的。了解这些基本机制将提供需要在颗粒水平上了解肺泡再生生物学并发展治疗需要的框架维护和恢复AT2祖细胞功能以驱动感染后维修和环境的策略压力。