Transcriptional Regulation of Lung Alveolar Regeneration

肺泡再生的转录调控

• 批准号: 10331870
• 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/10331870
• 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; Data; Defect; Development; Disease; Environment; Epigenetic Process; Epithelial; 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; base; 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; self-renewal; single-cell RNA sequencing; stem; 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且空间上不同的隔室组成，这些隔室对 损伤和疾病根据其细胞和细胞外组成而有不同的状态。肺泡 隔室或壁龛负责与外部环境的大部分气体交换 肺部是一个在肺部疾病（例如慢性阻塞性肺疾病）期间发生显着改变的区域 疾病（COPD）和特发性肺纤维化（IPF）。肺泡内至少有两个主要结构 成熟上皮细胞类型、肺泡 1 型 (AT1) 和肺泡 2 型细胞 (AT2) 以及各种 间充质细胞，包括 Pdgfra+/Axin2+ 间充质肺泡利基细胞 (MANC)、Axin2+ 肌成纤维细胞前体细胞（AMP）和定义不明确的血管内皮细胞群。尽管我们的 随着人们对构成肺泡的细胞类型的了解不断增加，我们对它们如何形成的信息知之甚少。 彼此沟通或他们的祖先分化的后代关系最终如何 受监管。为了解决这些问题，我们建议描述成熟成年人的遗传途径 肺，以更好地了解肺稳态的转录和表观遗传机制 再生。我们的初步数据已经确定了两种新的重要的肺泡转录调节因子 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向 AT1 细胞的分化。 Tfcp2l1 对于限制 AT2 分化为 AT1 谱系至关重要，而 Klf5 对于许可至关重要 AT2细胞在急性损伤后分化为AT1细胞的能力。此外，我们的初步数据表明 Tfcp2l1 标记 AEP 亚系的方式类似于 Lgr5 标记肠干细胞的方式。 总之，这些数据为肺泡的分子和细胞编排提供了重要的见解。 通过细胞类型特异性转录途径的参与实现稳态和再生 调节上皮细胞谱系的自我更新和分化。