ZIP8-dependent Zinc Metabolic Regulation in Alveolar Progenitor Cell Aging and Fibrosis

ZIP8 依赖性锌代谢调节肺泡祖细胞衰老和纤维化

• 批准号: 10672288
• 负责人: Carol Jiurong Liang
• 金额: $ 54.45万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672288
• 关键词: Acceleration; Acylation; Age; Aging; Alveolar; Anabolism; Biological Assay; Bleomycin; Cell Aging; Cell Compartmentation; Cell physiology; Cells; Characteristics; Complex; Coupled; Data; Disease; Elderly; Epithelial Cells; Epithelium; Failure; Fibrosis; Flow Cytometry; Functional disorder; Goals; Homeostasis; Human; Impairment; In Vitro; Incidence; Injury; Intervention; Knock-in; Link; Lung; Lung diseases; Mediating; Metabolic; Metabolism; Molecular; Mus; Natural regeneration; Organoids; Pathway interactions; Phenotype; Population; Predisposition; Premature aging syndrome; Process; Proteins; Pulmonary Fibrosis; Regulation; Rejuvenation; Reporting; Role; SIRT1 gene; Signal Pathway; Sirtuins; Testing; Zinc; Zinc supplementation; aged; aging population; alveolar epithelium; cell age; cell injury; epithelial repair; epithelial stem cell; exhaust; exhaustion; gain of function; genetic manipulation; healthspan; human old age (65+); idiopathic pulmonary fibrosis; improved; in vivo; injured; loss of function; lung injury; lung repair; mouse model; novel; premature; prevent; prototype; rapid growth; restoration; single-cell RNA sequencing; stem cell function; stem cells; zinc-binding protein

Abstract With the rapid growth of an aging population worldwide, the annual incidences of aging-associated lung diseases such as idiopathic pulmonary fibrosis (IPF), are increasing. Therefore, there is a great need to comprehensively investigate the complex process of lung aging and develop interventions to extend the health span of the elderly population. Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells that maintain epithelium homeostasis and repair the lung after injury. A characteristic of the aging lung is progenitor cell exhaustion and, in turn, impairs alveolar regeneration. Persistent epithelial cell injury coupled with inadequate alveolar epithelial repair due to progenitor cell failure results in a prototype of age-associated lung disease, IPF. In fact, it has been argued that IPF is a disease of premature aging of AEC2s. Hence, studies focusing on re-activating and/or expanding AEC2 progenitor cells in lung aging are needed. As we reported, AEC2 progenitor cells are exhausted in human IPF lungs. IPF AEC2s fail to regenerate in organoid assays relative to normal AEC2s. In our preliminary studies for this application, we found a decrease in AEC2 renewal capacity and a loss of AEC2 population occur during lung aging. We aimed to uncover the molecular mechanisms that contribute to impaired AEC2 renewal during aging, with the long-term goal of pointing the way to novel interventions that can rejuvenate aged AEC2s. We have found that: 1) The renewal capacity of AEC2s in 18-20 months old aged mouse lungs are reduced just as what we observed with IPF lungs; 2) Using single cell RNA-seq and flow cytometry, we identified a deficiency of a specific zinc transporter SLC39A8 (encoding ZIP8) in AEC2s from 18-20 months old aged mouse lungs and IPF lungs; 3) Sirtuin signaling pathway was downregulated in AEC2s from bleomycin-injured old mouse lungs and IPF lungs; 4) ZIP8 regulates AEC2 progenitor function through SIRT1 and ZIP8/SIRT1 axis is required for AEC2 renewal. In addition, we have generated a novel mouse model of Zip8 deficiency in AEC2 cells that reveals phenotypes of premature AEC2 aging. Based on these novel findings, we hypothesize that ZIP8 deficiency occurs in AEC2s with aging and downregulates SIRT1, thereby impairing AEC2 progenitor cell renewal. Furthermore, we propose that restoring critical components of the ZIP8/zinc/SIRT1 pathway will improve AEC2 progenitor activity and, thus maintain lung epithelial integrity and prevent age-associated lung diseases.

抽象的 随着全球老龄化人口的迅速增长，与衰老相关的肺部疾病的年发生率 例如特发性肺纤维化（IPF）正在增加。因此，非常需要全面 研究肺部衰老的复杂过程并制定干预措施以扩展老年人的健康跨度 人口。 2型肺泡上皮细胞（AEC2S）充当祖细胞，维持上皮 稳态并修复受伤后的肺部。衰老肺的一个特征是祖细胞衰竭， 反过来，会损害肺泡再生。持续性上皮细胞损伤，牙槽上皮不足 由于祖细胞衰竭而导致的修复导致与年龄相关的肺部疾病的原型，IPF。实际上，已经 认为IPF是AEC2过早衰老的疾病。因此，重点重新激活和/或的研究 需要在肺衰老中扩大AEC2祖细胞。 正如我们报道的那样，AEC2祖细胞在人IPF肺中耗尽。 IPF AEC2无法再生 类器官相对于正常AEC2S。在我们针对此应用的初步研究中，我们发现 在AEC2更新能力和肺老化期间AEC2种群损失的情况下。我们旨在发现 在衰老过程中有助于AEC2续约受损的分子机制，其长期目标是指向 可以使AEC2恢复活力的新颖干预措施的方式。我们发现：1）更新能力 在18-20个月大的小鼠肺中，AEC2降低了，就像我们在IPF肺部观察到的那样。 2）使用 单细胞RNA-seq和流式细胞仪，我们确定了特定锌转运蛋白SLC39A8的缺陷 （编码Zip8）在18-20个月大的老鼠肺和IPF肺中的AEC2中； 3）Sirtuin信号通路 来自博来霉素受伤的旧小鼠肺和IPF肺的AEC2中下调； 4）ZIP8调节AEC2 AEC2更新需要通过SIRT1和ZIP8/SIRT1轴的祖细胞功能。此外，我们还有 在AEC2细胞中生成了一种新型的Zip8缺乏的小鼠模型，该模型揭示了AEC2过早的表型 老化。基于这些新发现的结果，我们假设Zip8缺乏发生在AEC2中，衰老和 下调SIRT1，从而损害AEC2祖细胞续订。此外，我们建议 恢复Zip8/Zinc/sirt1途径的关键组件将改善AEC2祖细胞活性，从而改善 保持肺上皮完整性并预防与年龄相关的肺部疾病。