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.

摘要 随着全球人口老龄化的快速增长，与年龄相关的肺部疾病的年发病率 例如特发性肺纤维化（IPF），正在增加。因此，非常有必要全面 调查肺老化的复杂过程，并制定干预措施，以延长老年人的健康寿命 人口2型肺泡上皮细胞（AEC 2）作为维持上皮细胞的祖细胞发挥作用 内环境稳定和修复损伤后的肺。肺老化的一个特征是祖细胞衰竭， 进而损害肺泡再生。持续性上皮细胞损伤伴肺泡上皮细胞不足 由于祖细胞衰竭导致的修复导致年龄相关性肺病IPF的原型。事实上， 认为IPF是一种AEC 2过早老化的疾病。因此，研究重点是重新激活和/或 需要扩增肺老化中的AEC 2祖细胞。 正如我们所报道的，AEC 2祖细胞在人IPF肺中耗尽。IPF AEC 2不能再生， 相对于正常AEC 2的类器官测定。在我们对这一应用的初步研究中，我们发现 在肺老化期间发生AEC 2更新能力和AEC 2群体损失。我们的目标是揭露 分子机制，有助于受损的AEC 2更新在衰老过程中，与长期目标，指出 新的干预措施可以使老化的AEC 2恢复活力。我们发现：1）更新能力 18-20月龄小鼠肺中的AEC 2降低，正如我们在IPF肺中观察到的那样; 单细胞RNA-seq和流式细胞术，我们确定了一个特定的锌转运蛋白SLC 39 A8的缺陷 （编码ZIP 8）在来自18-20月龄小鼠肺和IPF肺的AEC 2中的表达; 在博来霉素损伤的老年小鼠肺和IPF肺的AEC 2中下调; 4）ZIP 8调节AEC 2 AEC 2更新需要通过SIRT 1和ZIP 8/SIRT 1轴的祖细胞功能。另外我们有 在AEC 2细胞中产生了一种新的Zip 8缺陷小鼠模型，该模型揭示了早产AEC 2的表型。 衰老基于这些新的发现，我们假设随着年龄的增长， 下调SIRT 1，从而损害AEC 2祖细胞更新。此外，我们建议， 恢复ZIP 8/锌/SIRT 1通路的关键组分将改善AEC 2祖细胞活性， 维持肺上皮完整性，预防与年龄相关的肺部疾病。