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.

项目摘要/摘要 呼吸道由管腔细胞组成，如棍状细胞和纤毛细胞，它们滋润和清洁呼吸道 分别为气道口。它们由基底细胞排列，在正常周转时充当腔细胞的前体细胞。 和损伤修复。祖细胞和腔/分化细胞比例的适当平衡对气道功能至关重要。 虽然已经确定了许多控制单个细胞命运的基因，但关于这一比例如何变化仍存在知识空白。 祖细胞和分化细胞的数量受到全球调控。在这项研究中，我们将研究呼吸道细胞如何 比率在发育中确立，在动态平衡中维持，并在受伤后恢复。 我们的切入点是Lon Protease 1(LONP1)，这是一种依赖于ATP的丝氨酸蛋白酶，它在 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和 线粒体健康。在先天性横隔疝(CDH)中发现LONP1基因突变 病人。CDH的死亡率很高，与肺发育不良和肺动脉高压有关。至 如果Lonp1在肺中起作用，我们在发育中的肺上皮和间充质中灭活它。 当间充质突变体存活到成体时，没有可识别的表型，而上皮突变体 表现出肺发育不全并在出生时死亡。出乎意料的是，这些突变体还表现出惊人的增长 基细胞以棒状细胞和纤毛细胞为代价。进一步的初步数据显示，综合指数上升 应激反应(ISR)途径基因，以及关键的组蛋白去甲基酶KDM6B的增加。在这项研究中， 我们将研究这种线粒体因子LONP1在通过ISR控制呼吸道细胞命运平衡中的作用 途径(目标1)、染色质调节剂(目标2)以及成人呼吸道内稳态和流感后- 致伤(目标3)。我们的发现将描绘出一条从线粒体蛋白酶到ER ISR再到 核染色质调节剂在根本上控制着呼吸道细胞的命运。