Epithelial Mesenchymal Transition in Pulmonary Fibrosis

肺纤维化中的上皮间质转化

基本信息

项目摘要

DESCRIPTION (provided by applicant): Alveolar epithelial cells (AEC) contribute to lung repair responses by proliferating, regulating matrix resorption, and presenting active TGF(1 to fibroblasts, promoting their conversion to myofibroblasts. AECs may also exercise their own plasticity to become fibroblast-like in their invasiveness and matrix production a process termed epithelial to mesenchymal-like transitions (EMT). While many lines of evidence link persistent active TGF(1 to the pathobiology of lung fibrosis, prolonged global inhibition of TGF(1 signaling is likely to have unacceptable toxicities. A more targeted therapeutic approach to blockade of TGF(1 signaling is needed. Recent findings identify a (1 integrin-dependent specific signaling pathway involving crosstalk between a tyrosine phosphorylated (-catenin (pY654) and Smad signaling that drives, and is required for, AEC EMT ex vivo and in vivo during fibrogenesis in mice. These observations lead to the hypothesis that dysregulated accumulation of nuclear pY654-(-catenin/pSmad2 complexes in AECs drives EMT, expands myofibroblasts, and results in progressive pulmonary fibrosis. This hypothesis is addressed in the application by a series of experiments designed to dissect and elucidate the key signaling events of EMT and myofibroblast expansion downstream of formation of (-catenin/pSmad2 complexes. It is postulated that pSmad2 functions as a key switch to either suppress EMT and fibrosis or, when complexed with pY654-(-catenin, switch on reprogramming leading to EMT. To test this hypothesis, mice with conditional deletion in vivo of the key components of the proposed signaling pathway will be used, along with a fate-mapping system to quantify EMT in vivo. Important gene targets of (-catenin/pSmad2 complexes in AECs and myofibroblasts will be defined through promoter analyses and direct DNA binding assays (chromatin immunoprecipitation). Biomarkers of the pathway driving EMT defined in mice will then be used to assess the activity of the (-catenin/pSmad2 pathway in human lungs. Collectively, these experiments should clarify important uncertainties regarding the role of EMT in pulmonary fibrosis, including Idiopathic Pulmonary Fibrosis (IPF). If the hypotheses prove largely correct, the studies should define a specific TGF(1-driven signaling pathway that could be quantified in IPF patients and serve as a basis for targeted therapy, avoiding the toxicities of prolonged global inhibition of TGF(1 signaling.
描述(由申请人提供):肺泡上皮细胞(AEC)通过增殖,调节基质吸收和呈现主动TGF来促进肺修复反应(1至成纤维细胞,促进其转化为肌纤维细胞。间充质样过渡(EMT),而许多证据链接持续的主动TGF(与肺纤维化的病理生物学1,全球抑制TGF的延长(1信号传导可能具有不可接受的毒性。酪氨酸磷酸化(-Catenin(Py654)和Smad信号传导,在小鼠纤维化期间驱动和必需的AEC EEC EMT和体内所必需。这些观察结果导致核PY654-(-Catenin/Psmad2 Complecters in aeecs in a aeecs and a e emef sefime y em em imef ysef seflive remt sefime imef ysef ysef ysef sefime y ybl y ybbl osef ysef seflive ysef sefime y rem try的假说肺纤维化。该假设在应用中通过一系列旨在解剖和阐明EMT和肌纤维细胞扩展的关键信号事件的一系列实验来解决。该假设将使用所提出的信号通路的关键组成部分的有条件缺失的小鼠,以及量化EMT在体内的命运映射系统(-catenin/psmad2 complection)在AEC中的重要基因靶标。然后,将使用小鼠定义的驱动EMT驱动EMT来评估人类肺中的( - 帕宁蛋白/PSMAD2途径的活性。总的来说,这些实验应阐明有关EMT在肺纤维化中的作用的重要不确定性,包括特发性肺纤维化(IPF)。如果假设在很大程度上是正确的,则研究应定义特定的TGF(1个驱动的信号通路,可以在IPF患者中进行量化,并作为靶向治疗的基础,避免了延长全球TGF的毒性(1个信号传导。

项目成果

期刊论文数量(44)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling.
  • DOI:
    10.1083/jcb.144.6.1285
  • 发表时间:
    1999-03-22
  • 期刊:
  • 影响因子:
    7.8
  • 作者:
    Wei, Y;Yang, X;Liu, Q;Wilkins, J A;Chapman, H A
  • 通讯作者:
    Chapman, H A
Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins.
尿激酶受体通过与多个整合素相互作用介导肺成纤维细胞附着和向临时基质蛋白的迁移。
Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy.
Epithelial responses to lung injury: role of the extracellular matrix.
Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors.
  • DOI:
    10.1158/2159-8290.cd-11-0240
  • 发表时间:
    2012-03
  • 期刊:
  • 影响因子:
    28.2
  • 作者:
    Sennino B;Ishiguro-Oonuma T;Wei Y;Naylor RM;Williamson CW;Bhagwandin V;Tabruyn SP;You WK;Chapman HA;Christensen JG;Aftab DT;McDonald DM
  • 通讯作者:
    McDonald DM
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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:
    $ 37.47万
  • 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:
    $ 37.47万
  • 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:
    9893639
  • 财政年份:
    2020
  • 资助金额:
    $ 37.47万
  • 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:
    $ 37.47万
  • 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:
    $ 37.47万
  • 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:
    $ 37.47万
  • 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:
    $ 37.47万
  • 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:
    $ 37.47万
  • 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:
    $ 37.47万
  • 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:
    $ 37.47万
  • 项目类别:

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了解和靶向流感引发的肺部炎症和病毒后疾病中的成纤维细胞激活
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阐明 I 型干扰素信号传导和巨噬细胞衍生炎症在病毒性肺炎幼年宿主中的作用
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