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:
  • 金额:
    $ 54.32万
  • 依托单位:
  • 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

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 衰老与肺部疾病的患病率增加有关,如特发性肺纤维化(IPF), 慢性阻塞性肺疾病(COPD)和急性肺损伤(ALI),然而, 导致与年龄相关的肺部疾病发病的衰老过程的机制尚未被证实。 被完全阐明。 在细胞水平上,只有有限的知识的因素,定义不同的肺细胞的健康老化, available.基于以上所述,我们建议创建人类老化肺(AHAL)图谱,包括 单个肺细胞类型的转录组图谱。这将填补现有的知识空白,并提供丰富的 为未来研究提供资源。转录差异可能反映了基因组的不稳定性, 线粒体功能障碍、衰老和SASP的标志物的响应和富集。我们也 研究线粒体自噬缺陷与衰老肺衰老相关的假说。 基于我们和其他研究,我们假设原发性自分泌衰老与年龄相关性衰老不同, 从转录上从年龄相关性肺部疾病中观察到的继发性旁分泌衰老程序 如IPF 我们提出了3个独立的目标来定义与年龄相关的肺部变化 目的1:绘制和表征人类肺部转录组学年龄相关变化。我们将执行 来自健康年轻人和老年人单细胞RNA序列(scRNAseq)和批量RNA序列(RNAseq 并建立了每种肺细胞类型以及细胞中转录组变化的综合图谱, 肺老化的人口变化。为了了解实足年龄和功能年龄的差异,我们将 还将鉴定的年龄相关基因特征与IPF的上叶和下叶基因特征进行比较, 相关的肺病。数据、结果以及肺细胞和转录组图谱将公开提供 通过我们将开发的基于云的综合门户网站。 目标2.探讨线粒体自噬在肺衰老和衰老表型中的作用。我们将 研究增加线粒体自噬减弱衰老肺中线粒体功能障碍的假设 并调节衰老表型。我们已经鉴定了线粒体去泛素化酶USP 30, 线粒体自噬的负调节因子,是线粒体自噬下降的关键因素。作为概念验证,我们将 使用原代小鼠研究USP 30在细胞衰老发展中的潜在致病作用 以及人细胞和USP 30-/-小鼠。 目标3。确定老化肺细胞区室中与衰老相关的变化。我们会研究如何 衰老的衰老细胞和它们的SASP库在细胞区室之间是不同的, 受伤后的重建我们将在来自年轻和老年肺的分离的衰老细胞中进行scRNAseq, 表征其细胞特异性衰老转录组。我们还将研究与年龄相关的衰老是否是 类似于在IPF肺细胞中观察到的衰老。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cellular Senescence in Lung Fibrosis.
  • DOI:
    10.3390/ijms22137012
  • 发表时间:
    2021-06-29
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Hernandez-Gonzalez F;Faner R;Rojas M;Agustí A;Serrano M;Sellarés J
  • 通讯作者:
    Sellarés J
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PANAGIOTIS V BENOS其他文献

PANAGIOTIS V BENOS的其他文献

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{{ truncateString('PANAGIOTIS V BENOS', 18)}}的其他基金

COPD SUBTYPES AND EARLY PREDICTION USING INTEGRATIVE PROBABILISTIC GRAPHICAL MODELS R01HL157879
使用集成概率图形模型进行 COPD 亚型和早期预测 R01HL157879
  • 批准号:
    10705838
  • 财政年份:
    2022
  • 资助金额:
    $ 54.32万
  • 项目类别:
COPD SUBTYPES AND EARLY PREDICTION USING INTEGRATIVE PROBABILISTIC GRAPHICAL MODELS R01HL157879
使用集成概率图形模型进行 COPD 亚型和早期预测 R01HL157879
  • 批准号:
    10689580
  • 财政年份:
    2022
  • 资助金额:
    $ 54.32万
  • 项目类别:
Interpretable graphical models for large multi-modal COPD data (R01HL159805)
大型多模态 COPD 数据的可解释图形模型 (R01HL159805)
  • 批准号:
    10689574
  • 财政年份:
    2021
  • 资助金额:
    $ 54.32万
  • 项目类别:
COPD SUBTYPES AND EARLY PREDICTION USING INTEGRATIVE PROBABILISTIC GRAPHICAL MODELS
使用综合概率图模型进行慢性阻塞性肺病亚型和早期预测
  • 批准号:
    10206417
  • 财政年份:
    2021
  • 资助金额:
    $ 54.32万
  • 项目类别:
Interpretable graphical models for large multi-modal COPD data (R01HL159805)
大型多模态 COPD 数据的可解释图形模型 (R01HL159805)
  • 批准号:
    10705824
  • 财政年份:
    2021
  • 资助金额:
    $ 54.32万
  • 项目类别:
Mapping Age-Related Changes in the Lung
绘制肺部与年龄相关的变化
  • 批准号:
    10440882
  • 财政年份:
    2019
  • 资助金额:
    $ 54.32万
  • 项目类别:
Mapping Age-Related Changes in the Lung
绘制肺部与年龄相关的变化
  • 批准号:
    10020437
  • 财政年份:
    2019
  • 资助金额:
    $ 54.32万
  • 项目类别:
Systems Biology of Diffusion Impairment in HIV
HIV扩散损伤的系统生物学
  • 批准号:
    9753361
  • 财政年份:
    2018
  • 资助金额:
    $ 54.32万
  • 项目类别:
Systems Biology of Diffusion Impairment in HIV
HIV扩散损伤的系统生物学
  • 批准号:
    10188612
  • 财政年份:
    2018
  • 资助金额:
    $ 54.32万
  • 项目类别:
Systems Level Causal Discovery in Heterogeneous TOPMed Data
异构 TOPMed 数据中的系统级因果发现
  • 批准号:
    9310591
  • 财政年份:
    2017
  • 资助金额:
    $ 54.32万
  • 项目类别:

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