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: 10318049
• 负责人: Xin Sun
• 金额: $ 52.8万
• 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/10318049
• 关键词: ARID1A gene; ATAC-seq; Address; Adult; Air; Airway Disease; Alveolar; Basal Cell; Birth; Cell Differentiation process; Cells; Chromatin; Chronic Obstructive Airway Disease; Congenital diaphragmatic hernia; Data; Development; Electron Transport; Endoplasmic Reticulum; Epithelial; Equilibrium; Evolution; Exhibits; FGF10 gene; Genes; Growth; Health; Homeostasis; Human; Individual; Influenza; Injury; Instruction; Knowledge; Link; Lung; Maintenance; Measures; Mesenchymal; Mesenchyme; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Mucous body substance; Mus; Mutate; Mutation; Nuclear; Oxides; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Play; 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; 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.

项目摘要/摘要 气道由腔细胞组成 气道分别。它们由在正常周转率中充当腔细胞的祖细胞的基底细胞衬里 和伤害修复。祖细胞和腔/分化细胞比率适当平衡对于气道功能至关重要。 尽管已经确定了许多控制单个细胞命运的基因，但知识差距仍然存在于比率的方式中 祖细胞和分化细胞的全球调节。在这项研究中，我们将研究气道电池如何 比率是在开发中建立的，维持体内平衡并在受伤后恢复。 我们的入口点是LON Protease 1（LONP1），这是一个依赖ATP的丝氨酸蛋白酶，可在 线粒体基质以降解氧化和错误折叠的蛋白质，从而控制蛋白质质量和 线粒体健康。 LONP1中的突变已在先天性diaphragmatratic Hernia（CDH）中鉴定出来 患者。 CDH具有与肺部发育不全和肺动脉高压相关的高死亡率。到 地址如果LONP1在肺中起作用，我们在发育中的肺上皮和间质中将其灭活。 虽然间充质突变体存活到没有可辨别表型的成年人，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明显的增加 基底细胞以俱乐部和纤毛细胞为代价。进一步的初步数据显示综合的增加 应力反应（ISR）途径基​​因，以及KDM6B的增加，KDM6B是一个关键组蛋白脱甲基酶。在这项研究中， 我们将研究该线粒体因子LONP1在通过ISR控制气道细胞命运平衡中的作用 途径（AIM 1），染色质调节剂（AIM 2）和成人气道体内平衡，并随后流感 诱发受伤（AIM 3）。我们的发现将描述从线粒体蛋白酶到ER ISR的新颖途径 气道细胞命运基本控制中的核染色质调节剂。