Mapping Age-Related Changes in the Lung

绘制肺部与年龄相关的变化

• 批准号: 10440882
• 负责人: PANAGIOTIS V BENOS
• 金额: $ 55.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440882
• 关键词: Acute Lung Injury; Age; Aging; Apoptosis; Atlases; Attenuated; Biological; Cell Aging; Cell Compartmentation; Cell Cycle Arrest; Cells; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Chronology; Complex; Coupled; Cyclin-Dependent Kinase Inhibitor 2A; Data; Development; Disease; Gene Expression; Genetic Transcription; Genomic Instability; Goals; Human; Impairment; Individual; Injury; Knowledge; Lobe; Lung; Lung diseases; Maps; Mitochondria; Molecular; Mus; Organism; Pathogenesis; Pathogenicity; Pathologic; Pathology; Phenotype; Physiological; Population; Predisposition; Prevalence; Process; Pulmonary Fibrosis; Pulmonary Pathology; RNA Sequences; Resistance; Resources; Role; Signal Pathway; Stimulus; Stress; Tissues; age related; aged; autocrine; base; biological adaptation to stress; cell type; cloud based; differential expression; genetic signature; healthy aging; idiopathic pulmonary fibrosis; mitochondrial autophagy; mitochondrial dysfunction; paracrine; programs; response; senescence; transcriptome; transcriptomics; web portal

ABSTRACT Aging is associated with increased prevalence of lung diseases, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and acute lung injury (ALI), however, the molecular mechanisms of the aging process that contribute to the pathogenesis of age-related lung diseases have not been completely elucidated. At a cellular level, only limited knowledge of the factors that define healthy aging of different lung cells is available. Based on the above, we propose to create an atlas of human aging lung (AHAL) consisting of transcriptomic maps of individual lung cell types. This will fill an existing knowledge gap and provide a rich resource for future research. Transcriptional differences might reflect genomic instability, alterations in stress responses and enrichment of markers of mitochondrial dysfunction, senescence and SASP. We also investigate the hypothesis that defective mitophagy is interconnected with senescence in the aging lung. Based on ours and other studies, we hypothesize that primary autocrine age-related senescence differs transcriptionally from the secondary paracrine senescence program observed in age-related lung diseases such as IPF We are proposing 3 independent aims to define age-related changes in the lung Aim 1: To map and characterize transcriptomic age-related changes in human lungs. We will perform single cell RNA sequence (scRNAseq) and bulk RNA sequence (RNAseq) from healthy young and aged human lungs and build a comprehensive atlas of transcriptomic changes in each lung cell type, as well as cell population shifts in aging lungs. In order to understand how chronological and functional ages differ, we will also compare the identified age-related gene signatures with those of the upper and lower lobe in IPF, an age- related lung disease. Data, results and lung cellular and transcriptome maps will be made publicly available through a cloud based comprehensive web portal that we will develop. Aim 2. To characterize the role of mitophagy in the aging lung and the senescence phenotype. We will investigate the hypotheses that augmenting mitophagy attenuates mitochondrial dysfunction in the aging lung and modulates the senescence phenotype. We have identified the mitochondrial deubiquitinase USP30, a negative regulator of mitophagy, as a key factor for mitophagy decline. As a proof of concept, we will investigate the potential pathogenic role of USP30 in the development of cell senescence using primary murine and human cells and USP30-/- mice. Aim 3. To identify senescence-related changes in aging lung cell compartments. We will examine how aging senescent cells and their SASP repertoire differ between cell compartments and contribute to tissue remodeling after injury. We will perform scRNAseq in isolated senescent cells from young and aged lungs and characterize their cell-specific senescent transcriptome. We will also investigate if age-related senescence is similar to senescence observed in cells from IPF lungs.!

抽象的 衰老与肺部疾病的患病率增加有关，例如特发性肺纤维化（IPF）， 然而，慢性阻塞性肺疾病（COPD）和急性肺损伤（ALI），但是分子 衰老过程的机制有助于与年龄相关的肺部疾病的发病机理 被完全阐明了。 在细胞水平上，只有对定义不同肺细胞健康衰老的因素的有限了解是 可用的。基于上述 单个肺细胞类型的转录组图。这将填补现有的知识差距，并提供富人 未来研究的资源。转录差异可能反映基因组不稳定性，压力改变 线粒体功能障碍，衰老和SASP的标记的反应和富集。我们也是 研究了有缺陷的线粒体与衰老肺衰老相互联系的假设。 根据我们的和其他研究，我们假设主要的自分泌年龄相关衰老有所不同 从与年龄有关的肺部疾病中观察到的次生旁分泌衰老计划的转录 例如IPF 我们提出了3个独立目标，以定义与年龄相关的肺部变化 目标1：绘制并表征人肺与转录组相关的变化。我们将表演 来自健康的年轻人和老年 人肺并建立每种肺部细胞类型的转录组变化的全面地图集，以及细胞 肺部衰老的人口变化。为了了解年代和功能年龄的不同，我们将 还将确定的与年龄相关的基因的特征与IPF中的上叶和下叶的特征进行比较， 相关肺部疾病。数据，结果以及肺细胞和转录组图将公开可用 通过将开发的基于云的综合网站。 目的2。表征线粒体在衰老肺和衰老表型中的作用。我们将 研究增加线粒体减弱线粒体功能障碍的假设 并调节衰老表型。我们已经确定了线粒体去泛素酶USP30，a 线粒体的负调节剂，是线粒体下降的关键因素。作为概念的证明，我们将 研究USP30在使用原代鼠的细胞衰老发展中的潜在致病作用 和人类细胞和USP30 - / - 小鼠。 目的3。确定与衰老肺部细胞室衰老相关的变化。我们将研究如何 衰老的衰老细胞及其SASP曲目在细胞室之间有所不同，并有助于组织 受伤后重塑。我们将在来自年轻肺和老年肺的孤立衰老细胞中执行scrnaseq， 表征其细胞特异性的衰老转录组。我们还将调查与年龄相关的衰老是否为 与IPF肺细胞中观察到的衰老相似。