Balancing Airway Progenitor versus Progeny: a Pathway from Mitochondria

平衡气道祖细胞与子代：线粒体的途径

• 批准号: 10673832
• 负责人: Xin Sun
• 金额: $ 51.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673832
• 关键词: ARID1A gene; ATAC-seq; Address; Adult; Air; Airway Disease; Alveolar; Basal Cell; Birth; Cell Differentiation process; Cells; Chromatin; Chronic Obstructive Pulmonary Disease; Congenital diaphragmatic hernia; Data; Development; Disparity; Electron Transport; Endoplasmic Reticulum; Epithelium; Equilibrium; Evolution; Exhibits; FGF10 gene; Genes; Growth; Health; Homeostasis; Human; Individual; Influenza; Injury; Knowledge; Link; Lung; Maintenance; Measures; Mesenchymal; Mesenchyme; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Mucous body substance; Mus; Mutate; Mutation; Nuclear; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Proteins; Pulmonary Hypertension; Quality Control; Regulator Genes; Role; Serine Protease; Signal Transduction; Tissues; Trachea; Virus Diseases; airway epithelium; biological adaptation to stress; cell type; endopeptidase La; epigenomics; histone demethylase; influenzavirus; injury and repair; keratin 5; lung injury; member; misfolded protein; mortality; mutant; neonatal pulmonary hypertension; novel; progenitor; seal; single-cell RNA sequencing; stem cells; transcription factor; transcriptomics; tumorigenesis

PROJECT SUMMARY/ABSTRACT The airway is composed of luminal cells such as club and ciliated cells that moisturize and clean the airway, respectively. They are lined by basal cells that serve as progenitors for luminal cells in normal turnover and injury repair. Proper balance of progenitor and luminal/differentiated cell ratio is critical for airway function. While many genes have been identified that control individual cell fate, knowledge gaps remain in how the ratio of progenitors and differentiated cells are globally regulated. In this study, we will investigate how airway cell ratio is established in development, maintained in homeostasis and restored following injury. Our entry point is Lon protease 1 (LONP1), an ATP-dependent serine protease that functions in the mitochondria matrix to degrade oxidized and misfolded proteins, thereby control protein quality and mitochondria health. Mutations in LONP1 has been identified in congenital diaphragmatic hernia (CDH) patients. CDH carries a high mortality rate associated with lung hypoplasia and pulmonary hypertension. To address if Lonp1 plays a role in lung, we inactivated it in the developing lung epithelium and mesenchyme. While the mesenchymal mutants survived to adult with no discernable phenotype, the epithelial mutants exhibited lung hypoplasia and died at birth. Unexpectedly, these mutants also exhibited a striking increase of basal cells at the expense of club and ciliated cells. Further preliminary data revealed an increase in integrated stress response (ISR) pathway genes, and an increase of KDM6B, a key histone demethylase. In this study, we will investigate the role of this mitochondria factor LONP1 in controlling airway cell fate balance via ISR pathway (Aim 1), chromatin regulators (Aim 2) and in adult airway homeostasis and following influenza- induced injury (Aim 3). Our findings will delineate a novel pathway from a mitochondria protease to ER ISR to nuclear chromatin regulators in the fundamental control of airway cell fate.

项目总结/摘要 气道是由管腔细胞，如俱乐部和纤毛细胞，滋润和清洁的 气道，分别。它们由基底细胞排列，基底细胞在正常周转中充当管腔细胞的祖细胞 和损伤修复。祖细胞和管腔/分化细胞比率的适当平衡对于气道功能至关重要。 虽然已经确定了许多控制单个细胞命运的基因，但在比例如何变化方面仍然存在知识空白。 祖细胞和分化细胞的生长受到全面调控。在本研究中，我们将研究气道细胞如何 比例在发育中建立，维持稳态并在损伤后恢复。 我们的切入点是Lon蛋白酶1（LONP 1），一种ATP依赖性丝氨酸蛋白酶，在细胞内起作用。 线粒体基质降解氧化和错误折叠的蛋白质，从而控制蛋白质质量， 线粒体健康LONP 1的突变已在先天性腹股沟疝（CDH）中被确定。 患者CDH具有与肺发育不良和肺动脉高压相关的高死亡率。到 为了解决Lonp1是否在肺中起作用，我们在发育中的肺上皮和间充质中将其灭活。 虽然间充质突变体存活至成年，没有可辨别的表型，但上皮突变体 表现出肺发育不全并在出生时死亡。出乎意料的是，这些突变体也表现出惊人的增加， 以棒状细胞和纤毛细胞为代价的基底细胞。进一步的初步数据显示， 应激反应（ISR）途径基因，以及关键组蛋白去甲基化酶KDM6B的增加。在本研究中， 我们将研究这种线粒体因子LONP 1在通过ISR控制气道细胞命运平衡中的作用 通路（Aim 1），染色质调节因子（Aim 2）和成人气道稳态和流感后- 致伤（目标3）。我们的研究结果将描绘一个新的途径，从线粒体蛋白酶到ER ISR， 核染色质调节剂在气道细胞命运的基本控制。