Deciphering the role of p16INK4A+ fibroblasts in lung fibrosis

解读 p16INK4A 成纤维细胞在肺纤维化中的作用

基本信息

  • 批准号:
    10340480
  • 负责人:
  • 金额:
    $ 55.69万
  • 依托单位:
  • 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:
    2022-02-01 至 2025-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Aging is one of the biggest risk factors for many chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). However, uncertainties remain as to how age-related processes contribute to the pathogenesis of IPF, particularly in deciphering the cell types that might play a role in both aging and fibrotic transformation. Senescence, a cellular state characterized by an irreversible cell cycle arrest and other morphologic transformations, is thought to be a cellular phenotype that becomes increasingly prevalent in aged organs, contributing to the decline in function over time. p16INK4A, a tumor suppressor, is one of the best-studied biomarkers of senescent cells in vitro and in vivo. Numerous genetic models have been built to remove p16INK4A+ cells from tissues, demonstrating a functional role for these cells in promoting age-related pathologies such as lung fibrosis. Despite the knowledge gained from strategies that remove p16INK4A+ cells, deletion of these cells precludes the identification and functional characterization of p16INK4A+ cells in vivo, leaving a large gap in our understanding of how senescent cells might behave in tissues rather than in a culture dish. To address this, we constructed a novel genetic reporter of senescence by engineering an amplified fluorescent tag driven by expression of p16INK4A (mouse referred to as INK4A H2B-GFP Reporter-In-Tandem, or INKBRITE) to isolate and characterize p16INK4A+ cells in vivo and ex vivo. To our surprise, we were able to identify p16INK4A+ fibroblasts in young and healthy lungs that contribute to scar-forming cells in areas of fibrotic remodeling. Furthermore, p16INK4A+ cells are able to alter the epithelial progenitor microenvironment and alter stem cell regenerative outcomes. This led us to the hypothesis that p16INK4A+ fibroblasts are capable of contributing to fibrosis by forming scars and inducing an pathologic epithelial response, and the INKBRITE reporter could be leveraged as a screening platform to identify compounds that more precisely target p16INK4A+ fibroblasts in vivo. Through the use of single cell RNA sequencing, adoptive cell transfers, lineage tracing, high-content imaging, and various methodologies outlined in this proposal, we aim to better define the cellular contribution of p16INK4A+ fibroblasts to fibrotic transformation, and define agents that might better remove it from tissues.
项目摘要/摘要 衰老是许多慢性肺部疾病的最大危险因素之一,包括特发性肺纤维化。 (IPF)。然而,年龄相关的过程如何在IPF的发病机制中发挥作用仍然存在不确定性。 特别是在破译可能在衰老和纤维化转化中发挥作用的细胞类型方面。 衰老,一种细胞状态,以不可逆的细胞周期停滞和其他形态为特征 转化,被认为是一种细胞表型,在老化的器官中变得越来越普遍, 导致功能随着时间的推移而下降。P16INK4a,一种肿瘤抑制因子,是研究最多的研究之一 衰老细胞在体外和体内的生物标志物。已经建立了许多遗传模型来去除p16INK4A+ 来自组织的细胞,展示了这些细胞在促进与年龄相关的病理方面的功能作用,如 肺纤维化。尽管从移除p16INK4A+细胞的策略中获得了知识,但删除这些细胞 排除了体内p16INK4A+细胞的鉴定和功能鉴定,在我们的 了解衰老细胞在组织中的行为,而不是在培养皿中的行为。为了解决这个问题,我们 通过设计一个扩增的荧光标签来构建一个新的衰老遗传报告 P16INK4A(小鼠称为Ink4a H2B-GFP Reporter-in-Tandem,或INKBRITE)的表达 P16INK4A+细胞的体内外鉴定。令我们惊讶的是,我们能够鉴定出p16INK4A+成纤维细胞 年轻健康的肺,有助于纤维化重塑区域的疤痕形成细胞。此外, P16INK4a+细胞能够改变上皮祖细胞微环境,改变干细胞再生 结果。这导致我们假设p16INK4A+成纤维细胞能够通过以下方式促进纤维化 形成疤痕并诱导病理上皮反应,INKBRITE报告可以作为杠杆 一个筛选平台,以确定更准确地靶向体内p16INK4A+成纤维细胞的化合物。通过 使用单细胞RNA测序、过继细胞转移、谱系追踪、高含量成像和各种 在这项提案中概述的方法学,我们的目标是更好地定义p16INK4A+成纤维细胞的细胞贡献 纤维化转化,并定义可能更好地将其从组织中移除的试剂。

项目成果

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Tien Peng其他文献

Tien Peng的其他文献

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{{ truncateString('Tien Peng', 18)}}的其他基金

Deciphering the role of p16INK4A+ fibroblasts in lung fibrosis
解读 p16INK4A 成纤维细胞在肺纤维化中的作用
  • 批准号:
    10559515
  • 财政年份:
    2022
  • 资助金额:
    $ 55.69万
  • 项目类别:
Mesenchymal modulation of epithelial metaplasia in lung fibrosis
肺纤维化中上皮化生的间充质调节
  • 批准号:
    10548148
  • 财政年份:
    2021
  • 资助金额:
    $ 55.69万
  • 项目类别:
Mesenchymal modulation of epithelial metaplasia in lung fibrosis
肺纤维化中上皮化生的间充质调节
  • 批准号:
    10331772
  • 财政年份:
    2021
  • 资助金额:
    $ 55.69万
  • 项目类别:
Mesenchymal modulation of epithelial metaplasia in lung fibrosis
肺纤维化中上皮化生的间充质调节
  • 批准号:
    10095587
  • 财政年份:
    2021
  • 资助金额:
    $ 55.69万
  • 项目类别:
Maintenance of the alveolar niche in emphysema
肺气肿肺泡微环境的维护
  • 批准号:
    9768539
  • 财政年份:
    2018
  • 资助金额:
    $ 55.69万
  • 项目类别:
Maintenance of the alveolar niche in emphysema
肺气肿肺泡微环境的维护
  • 批准号:
    10208941
  • 财政年份:
    2018
  • 资助金额:
    $ 55.69万
  • 项目类别:
Maintenance of the alveolar niche in emphysema
肺气肿肺泡微环境的维护
  • 批准号:
    10435711
  • 财政年份:
    2018
  • 资助金额:
    $ 55.69万
  • 项目类别:
The roles of Hedgehog signaling in pulmonary vascular development and remodeling
Hedgehog信号在肺血管发育和重塑中的作用
  • 批准号:
    9118452
  • 财政年份:
    2014
  • 资助金额:
    $ 55.69万
  • 项目类别:
The roles of Hedgehog signaling in pulmonary vascular development and remodeling
Hedgehog信号在肺血管发育和重塑中的作用
  • 批准号:
    9300965
  • 财政年份:
    2014
  • 资助金额:
    $ 55.69万
  • 项目类别:
The roles of Hedgehog signaling in pulmonary vascular development and remodeling
Hedgehog信号在肺血管发育和重塑中的作用
  • 批准号:
    8766755
  • 财政年份:
    2014
  • 资助金额:
    $ 55.69万
  • 项目类别:

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