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.

摘要 呼吸系统由多个独特且空间上不同的隔室组成， 损伤和疾病的状态基于它们的细胞和细胞外组成而不同。肺泡 隔室或壁龛负责与外部环境的大部分气体交换， 在慢性阻塞性肺疾病（如慢性阻塞性肺疾病）期间， 疾病（COPD）和特发性肺纤维化（IPF）。在肺泡内，至少有两个主要的 成熟上皮细胞类型，肺泡1型（AT 1）和肺泡2型细胞（AT 2），以及各种 间充质细胞，包括Pdgfra+/Axin 2+间充质肺泡小生境细胞（MANC）、Axin 2 + 肌成纤维细胞前体细胞（AMP）和定义不清的血管内皮细胞群。尽管我们 随着对构成肺泡的细胞类型的了解的增加，我们对它们如何在体内生长的信息很少。 或者它们的祖先-分化的后代关系最终是如何相互沟通的。 监管.为了解决这些问题，我们建议描述成熟成虫的遗传途径， 为了更好地理解肺内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个新的和重要的转录调控因子的肺泡 上皮稳态和再生：Tfcp 2l 1和Klf 5。我们的初步数据表明，Tfcp 2l 1和Klf 5 以相反的方式调节AEP和AT 2细胞的自我更新及其向AT 1细胞的分化。 Tfcp 2l 1在限制AT 2分化为AT 1谱系中是必需的，而Klf 5在许可AT 2分化为AT 1谱系中是必需的。 AT 2细胞在急性损伤后分化为AT 1细胞的能力。此外，我们的初步数据表明， Tfcp 2l 1标记AEP亚系的方式与Lgr 5标记肠干细胞的方式相似。 总之，这些数据提供了重要的见解，分子和细胞的编排肺泡 通过细胞类型特异性转录途径的参与， 调节上皮细胞谱系的自我更新和分化。