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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的随着全球人口老龄化的迅速增长，与衰老相关的肺部疾病的每年发病率例如特发性肺纤维化（IPF）正在增加。因此，非常有必要全面研究肺部衰老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 (AEC2) 充当维持上皮的祖细胞损伤后的肺部稳态和修复。肺部衰老的一个特征是祖细胞衰竭，反过来，会损害肺泡再生。持续的上皮细胞损伤加上肺泡上皮细胞不足由于祖细胞衰竭导致的修复导致了与年龄相关的肺病（IPF）的原型。事实上，已经认为 IPF 是 AEC2 过早衰老的疾病。因此，研究的重点是重新激活和/或肺衰老过程中需要扩大 AEC2 祖细胞。正如我们所报道的，人 IPF 肺部的 AEC2 祖细胞已耗尽。 IPF AEC2 无法再生相对于正常 AEC2 的类器官测定。在我们对此应用的初步研究中，我们发现减少了 AEC2 更新能力的降低和 AEC2 群体的损失发生在肺衰老过程中。我们的目的是揭开衰老过程中导致 AEC2 更新受损的分子机制，长期目标是指出寻找可以使老化的 AEC2 恢复活力的新干预措施的方法。我们发现： 1）更新能力 18-20 个月大的小鼠肺部的 AEC2 减少，正如我们在 IPF 肺部观察到的那样； 2）使用单细胞 RNA-seq 和流式细胞术，我们发现了特定锌转运蛋白 SLC39A8 的缺陷（编码ZIP8）存在于18-20月龄小鼠肺和IPF肺的AEC2中； 3) Sirtuin信号通路博莱霉素损伤的老小鼠肺和 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，我们还有建立了 AEC2 细胞中 Zip8 缺陷的新型小鼠模型，揭示了 AEC2 过早的表型老化。基于这些新发现，我们假设随着衰老和衰老，AEC2 中会出现 ZIP8 缺陷。下调 SIRT1，从而损害 AEC2 祖细胞更新。此外，我们建议恢复 ZIP8/zinc/SIRT1 通路的关键成分将提高 AEC2 祖细胞活性，从而维持肺上皮完整性并预防与年龄相关的肺部疾病。