Transcriptional Regulation of Lung Alveolar Regeneration

肺泡再生的转录调控

• 批准号: 10549771
• 负责人: EDWARD E MORRISEY
• 金额: $ 57.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549771
• 关键词: ATAC-seq; Acute; Acute Lung Injury; Address; Adult; Alveolar; Alveolus; Area; Automobile Driving; Behavior; Biological Assay; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; Chronic; Chronic Disease; Chronic Obstructive Pulmonary Disease; Communication; Data; Defect; Development; Disease; Environment; Epigenetic Process; Epithelial Cells; Family; Gases; Genetic; Genetic Transcription; Goals; Histologic; Homeostasis; Human; Injury; Intestines; Knowledge; LGR5 gene; Laboratories; Licensing; Lung; Lung diseases; Mesenchymal; Molecular; Mus; Myofibroblast; Natural regeneration; Organoids; Pathway interactions; Pattern; Population; Pulmonary alveolar structure; Reporter; Respiratory System; Role; Specific qualifier value; Target Populations; Transcriptional Regulation; Vascular Endothelial Cell; Viral; WNT Signaling Pathway; Work; alveolar epithelium; alveolar homeostasis; cell behavior; cell regeneration; cell type; epithelial stem cell; epithelium regeneration; extracellular; idiopathic pulmonary fibrosis; insight; loss of function; lung development; lung injury; postnatal; precursor cell; progenitor; repaired; response to injury; restraint; self-renewal; single-cell RNA sequencing; stem cells; transcription factor; transcription regulatory network; transcriptome sequencing

ABSTRACT The respiratory system is comprised of multiple unique and spatially distinct compartments that respond to injury and diseases states differently based on their cellular and extracellular composition. The alveolar compartment or niche is responsible for the majority of gas exchange with the external environment in the lungs and is an area that is dramatically altered during lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Within the alveolus, there are at least two major mature epithelial cell types, alveolar type 1 (AT1) and alveolar type 2 cells (AT2), as well as various mesenchymal cells including Pdgfra+/Axin2+ mesenchymal alveolar niche cells (MANCs), Axin2+ myofibroblast precursor cells (AMPs), and poorly defined vascular endothelial cell populations. Despite our increasing knowledge of the cell types that comprise the lung alveolus, we have little information on how they communicate with each other or how their progenitor-differentiated progeny relationships are ultimately regulated. To address these questions, we propose to characterize the genetic pathways of the mature adult lung to better understand the transcriptional and epigenetic mechanisms underlying lung homeostasis and regeneration. Our preliminary data has identified two new and important transcriptional regulators of alveolar epithelial homeostasis and regeneration: Tfcp2l1 and Klf5. Our preliminary data suggest that Tfcp2l1 and Klf5 regulate the self-renewal of AEP and AT2 cells and their differentiation into AT1 cells, in opposing manners. Tfcp2l1 is essential in restricting AT2 differentiation into the AT1 lineage whereas Klf5 is essential for licensing the ability of AT2 cells to differentiate into AT1 cells after acute injury. Moreover, our preliminary data suggests that Tfcp2l1 marks the AEP sublineage in a manner similar to how Lgr5 marks the intestinal stem cell. Together, these data provide critical insight into the molecular and cellular orchestration of alveolar homeostasis and regeneration through the engagement of cell type specific transcriptional pathways that regulate self-renewal and differentiation of epithelial cell lineages.

抽象的 呼吸系统由多个独特和空间不同的隔室组成 损伤和疾病根据其细胞和细胞外组成的方式不同。牙槽 车厢或利基市场负责大多数与外部环境的天然气交换 肺部，是肺部疾病（例如慢性阻塞性肺部）发生的区域 疾病（COPD）和特发性肺纤维化（IPF）。在肺泡中，至少有两个主要 成熟的上皮细胞类型，牙槽1（AT1）和2型牙槽2型细胞（AT2）以及各种 间充质细胞，包括PDGFRA+/AXIN2+间充质肺泡细胞（MANC），AXIN2+ 肌纤维细胞前体细胞（AMP）和较差的血管内皮细胞群体。尽管我们 越来越多地了解构成肺肺泡的细胞类型，我们几乎没有信息 彼此交流，或者其祖细胞分化的后代关系最终是如何的 受监管。为了解决这些问题，我们建议表征成熟成人的遗传途径 肺部更好地了解肺稳态和肺部的转录机制和 再生。我们的初步数据已经确定了牙槽的两个新的和重要的转录调节剂 上皮稳态和再生：TFCP2L1和KLF5。我们的初步数据表明TFCP2L1和KLF5 以相反的方式调节AEP和AT2细胞的自我更新及其分化为AT1细胞。 TFCP2L1对于将AT2分化为AT1谱系至关重要，而KLF5对于许可至关重要 急性损伤后AT2细胞分化为AT1细胞的能力。此外，我们的初步数据建议 TFCP2L1以类似于LGR5标记肠道干细胞的方式标记AEP sublineage。 总之，这些数据为牙槽的分子和细胞架构提供了关键的见解 稳态和再生通过细胞类型的特定转录途径的参与 调节上皮细胞谱系的自我更新和分化。