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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要气道由管腔细胞组成，例如棒状细胞和纤毛细胞，它们可以滋润和清洁呼吸道气道，分别。它们由基底细胞排列，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/分化细胞比例的适当平衡对于气道功能至关重要。虽然许多基因已被发现控制个体细胞的命运，但在如何控制个体细胞命运方面仍然存在知识差距。祖细胞和分化细胞受到全球调控。在这项研究中，我们将研究气道细胞如何该比率在发育过程中建立，维持稳态并在受伤后恢复。我们的切入点是 Lon 蛋白酶 1 (LONP1)，一种 ATP 依赖性丝氨酸蛋白酶，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。在先天性膈疝 (CDH) 中发现了 LONP1 突变患者。 CDH 具有与肺发育不全和肺动脉高压相关的高死亡率。到如果 Lonp1 在肺中发挥作用，我们将其在发育中的肺上皮和间质中灭活。虽然间充质突变体存活至成年且没有可辨别的表型，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基底细胞以牺牲球杆细胞和纤毛细胞为代价。进一步的初步数据显示综合性有所增加应激反应 (ISR) 通路基因，以及关键组蛋白去甲基化酶 KDM6B 的增加。在这项研究中，我们将研究线粒体因子 LONP1 通过 ISR 控制气道细胞命运平衡的作用途径（目标 1）、染色质调节因子（目标 2）以及成人气道稳态和流感后的影响诱发伤害（目标 3）。我们的研究结果将描绘出一条从线粒体蛋白酶到 ER ISR 的新途径核染色质调节因子从根本上控制气道细胞的命运。