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:
    10559515
  • 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.
项目总结/摘要 衰老是包括特发性肺纤维化在内的许多慢性肺部疾病的最大危险因素之一 (森林小组)。然而,关于年龄相关过程如何促进IPF的发病机制仍不确定, 特别是在破译可能在衰老和纤维化转化中起作用的细胞类型方面。 衰老是一种以不可逆的细胞周期停滞和其他形态学改变为特征的细胞状态。 转化,被认为是一种细胞表型,在老年器官中变得越来越普遍, 随着时间的推移导致功能下降。p16 INK 4A是一种肿瘤抑制因子, 体外和体内衰老细胞的生物标志物。已经建立了许多遗传模型来去除p16 INK 4A + 细胞,证明了这些细胞在促进年龄相关的病理学中的功能作用, 肺纤维化尽管从去除p16 INK 4A+细胞的策略中获得了知识,但这些细胞的缺失 排除了p16 INK 4A+细胞在体内的鉴定和功能表征,在我们的研究中留下了很大的空白。 了解衰老细胞在组织中而不是在培养皿中的行为。为了解决这个问题,我们 构建了一个新的衰老基因报告基因,通过工程化一个由 表达p16 INK 4A(小鼠称为INK 4AH 2B-GFP串联报告子,或INKBRITE)以分离和 在体内和离体表征p16 INK 4A+细胞。令我们惊讶的是,我们能够在100例乳腺癌中鉴定出p16 INK 4A+成纤维细胞。 年轻和健康的肺部,有助于纤维化重塑区域的瘢痕形成细胞。此外,委员会认为, p16 INK 4A+细胞能够改变上皮祖细胞微环境并改变干细胞再生能力。 结果。这导致我们假设p16 INK 4A+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性上皮反应,INKBRITE报告基因可以作为 一个筛选平台,以确定更精确地靶向体内p16 INK 4A+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、高内涵成像和各种 在本提案中概述的方法,我们的目标是更好地确定p16 INK 4A+成纤维细胞的细胞贡献 纤维化转化,并确定可能更好地将其从组织中去除的药物。

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:
    10340480
  • 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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