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Mapping Age-Related Changes in the Lung

绘制肺部与年龄相关的变化

基本信息

批准号：
10473606
负责人：
PANAGIOTIS V BENOS
金额：
$ 54.32万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473606
关键词：
Acute Lung Injury Age Aging Apoptosis Atlases Attenuated Cell Aging Cell Compartmentation Cell Cycle Arrest Cells Chronic Chronic Obstructive Pulmonary 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

项目摘要

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.!

摘要