Program to promote lung regeneration and block fibrosis

促进肺再生和阻止纤维化的计划

基本信息

项目摘要

ABSTRACT The goal of this research program is to understand the interactions between lung epithelial and mesenchymal cells in sufficient detail to deliver new therapeutic interventions in pulmonary fibrosis, a process without disease modifying therapies. This program is anchored by a recently funded RO1 to further elucidate mechanisms of a fibroblast-specific trihydroxyphenolic inhibitor of LOXL2 and TGFR1 with potent in vivo anti-fibrotic effects. We will test one of these, EGCG, in a proof of principle clinical trial. Unpublished data show reversal of a core set of pro-fibrotic tissue biomarkers in IPF patients given EGCG two weeks prior to diagnostic lung biopsy. The R35 mechanism allows us to integrate our capacity to attenuate fibrosis with the broader issue of defective epithelial regeneration in IPF, a competing process with fibrogenesis. This is sometimes simplified in the idea repeated epithelial injury leads to stem cell failure thereby creating an unrelenting pro-fibrotic environment. But the lung is resilient with multiple, spatially distinct progenitor cells whose identify and integrative functions remain poorly understood, especially in IPF patients. This paradigm also overlooks the potentially critical contribution of pro-fibrotic mesenchymal cells in driving further loss of the epithelium. Type II cells in the IPF lung at the time of lung transplant are less than 15% of that present in a normal lung. The program will focus on further elucidating the potential of resident epithelial stem/progenitors in mouse and human to regenerate alveolar integrity. In parallel, mechanisms by which activated mesenchymal cells contribute to dysfunction and loss of these epithelial progenitors will be defined. We plan to leverage fibroblast-specific TGFb1 inhibition to study its impact on progenitor cells in both animal models and in IPF patients, for example by single cell RNA- seq of tissues from untreated and EGCG treated patients. We envision a future small molecule image-based screen to identify agents that improve type II cell health in cultured epithelial/fibroblast organoids. Overall the R35 program gives us the opportunity to integrate all of these directions into a centrally themed, multidimensional approach that should transform how we view lung regeneration and fibrogenesis and how we treat patients with unrelenting fibrosis.
摘要

项目成果

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Harold A Chapman其他文献

Harold A Chapman的其他文献

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{{ truncateString('Harold A Chapman', 18)}}的其他基金

Phase 1 study of oral epigallocatechin-3-gallate (EGCG) in IPF patients
IPF 患者口服表没食子儿茶素-3-没食子酸酯 (EGCG) 的 1 期研究
  • 批准号:
    10702133
  • 财政年份:
    2022
  • 资助金额:
    $ 96.55万
  • 项目类别:
Phase 1 study of oral epigallocatechin-3-gallate (EGCG) in IPF patients
IPF 患者口服表没食子儿茶素-3-没食子酸酯 (EGCG) 的 1 期研究
  • 批准号:
    10418169
  • 财政年份:
    2022
  • 资助金额:
    $ 96.55万
  • 项目类别:
Program to promote lung regeneration and block fibrosis
促进肺再生和阻止纤维化的计划
  • 批准号:
    10570862
  • 财政年份:
    2020
  • 资助金额:
    $ 96.55万
  • 项目类别:
Epithelial stem/progenitor cells as repair agents in diffuse alveolar damage
上皮干/祖细胞作为弥漫性肺泡损伤的修复剂
  • 批准号:
    10181019
  • 财政年份:
    2016
  • 资助金额:
    $ 96.55万
  • 项目类别:
Epithelial stem/progenitor cells as repair agents in diffuse alveolar damage
上皮干/祖细胞作为弥漫性肺泡损伤的修复剂
  • 批准号:
    9355470
  • 财政年份:
    2016
  • 资助金额:
    $ 96.55万
  • 项目类别:
Epithelial stem/progenitor cells as repair agents in diffuse alveolar damage
上皮干/祖细胞作为弥漫性肺泡损伤的修复剂
  • 批准号:
    10418711
  • 财政年份:
    2016
  • 资助金额:
    $ 96.55万
  • 项目类别:
Epithelial Stem/Progenitor Cells in Repair of the Injured Lung
上皮干细胞/祖细胞修复受损肺
  • 批准号:
    9109038
  • 财政年份:
    2015
  • 资助金额:
    $ 96.55万
  • 项目类别:
Identification, Isolation, and Reprogramming Alveolar Epithelial Progenitor Cells
肺泡上皮祖细胞的鉴定、分离和重编程
  • 批准号:
    7676645
  • 财政年份:
    2008
  • 资助金额:
    $ 96.55万
  • 项目类别:
Urokinase Receptor Integrin Interactions in Lung Cancer
肺癌中尿激酶受体整合素相互作用
  • 批准号:
    7318124
  • 财政年份:
    2007
  • 资助金额:
    $ 96.55万
  • 项目类别:
Urokinase Receptor Integrin Interactions in Lung Cancer
肺癌中尿激酶受体整合素相互作用
  • 批准号:
    8079454
  • 财政年份:
    2007
  • 资助金额:
    $ 96.55万
  • 项目类别:

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