Targeting the Apoptosis-Resistant Pulmonary Myofibroblast

靶向抗凋亡肺肌成纤维细胞

基本信息

  • 批准号:
    8516090
  • 负责人:
  • 金额:
    $ 36.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-01 至 2016-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an incurable fatal disease with increasing incidence and mortality. Despite recent coordinated attempts to rapidly translate findings which have been validated in vitro and in preclinical models into biologically promising interventions, there have been no major therapeutic breakthroughs. A final common pathway for the destructive remodeling which characterizes fibrosis is the apoptosis-resistant myofibroblast, which both creates and responds to an altered mediator and matrix microenvironment, thus perpetuating fibrogenesis. Halting the development of the myofibroblast phenotype, or reversing it once established, offers the best hope of successfully treating IPF. The cell surface glycoprotein Thy-1, a known tumor suppressor which acts as a context-dependent regulator of cell phenotype, is silenced in the myofibroblasts within fibroblastic foci, the signature histopathologic lesions in IPF, the presence of which portends a poor prognosis. Absence of Thy-1 in cultured lung fibroblasts promotes proliferation, cytokine and growth factor expression and responsiveness, migration, myofibroblastic differentiation, and resistance to apoptosis, all reversible upon re-expression of Thy-1. Thy-1 interacts with alpha v integrins and syndecan 4 at the cell surface, modulating cell-cell and cell-matrix interactions and mechanical coupling, to inhibit TGF-beta activation and myofibroblastic differentiation. The effects of Thy-1 on the myofibroblast phenotype are broad, including: decreased expression of a number of muscle-specific proteins and myogenic transcription factors, inhibition of contractility, and promotion of apoptosis. Furthermore, some of the functions of Thy-1 can be recapitulated by the administration of soluble Thy-1, and preliminary data demonstrate that soluble Thy-1 reverses established fibrosis in a mouse model, indicating that Thy-1 itself can be used or modified for therapeutic benefit. Taken together, this knowledge leads us to the overall hypothesis that Thy-1-mediated signaling broadly suppresses myofibroblastic transformation and promotes apoptosis, restoring homeostatic function in lung fibroblasts. Improved understanding of the molecular mechanisms involved will uncover novel strategies for reversing the pathogenic myofibroblast phenotype in IPF and other fibrotic disorders. In vitro and in vivo models based on heterogeneity and targeted disruption of Thy-1 offer excellent opportunities for defining myofibroblast-targeting strategies, as outlined in the following specific aims: Aim 1: To define the mechanisms by which Thy-1- inhibits myofibroblastic differentiation of lung fibroblasts; Aim 2: To define the mechanisms by which Thy-1 promotes myofibroblast apoptosis; and Aim 3: To harness Thy-1-modulated signaling to reverse the apoptosis-resistant myofibroblast phenotype in vivo. Significance: Because Thy-1 modulates multiple signaling pathways critical to fibrogenesis, capitalizing on its function is more attractive than targeting a single pathway, which has been shown to be an ineffective approach in IPF. The proposed studies will thus define mechanisms by which Thy-1 suppresses profibrotic differentiation of lung fibroblasts, and translate that knowledge into innovative therapeutic interventions for fibrotic lung disease.
描述(由申请方提供):特发性肺纤维化(IPF)是一种无法治愈的致死性疾病,其发病率和死亡率不断增加。尽管最近的协调努力,以迅速转化的发现,已在体外和临床前模型验证生物学有前途的干预措施,一直没有重大的治疗突破。纤维化特征性破坏性重塑的最后一个共同途径是抗纤维化的肌成纤维细胞,其产生并响应于改变的介质和基质微环境,从而使纤维发生永久化。停止肌成纤维细胞表型的发展,或一旦建立就逆转它,为成功治疗IPF提供了最大的希望。细胞表面糖蛋白Thy-1是一种已知的肿瘤抑制因子,作为细胞表型的背景依赖性调节因子,在成纤维细胞灶内的肌成纤维细胞中沉默,成纤维细胞灶是IPF的标志性组织病理学病变,其存在预示着预后不良。培养的肺成纤维细胞中Thy-1的缺乏促进增殖、细胞因子和生长因子表达和反应性、迁移、肌成纤维细胞分化和抗凋亡,所有这些在Thy-1的再表达后都是可逆的。Thy-1在细胞表面与α v整联蛋白和多配体蛋白聚糖4相互作用,调节细胞-细胞和细胞-基质相互作用, 机械偶联,以抑制TGF-β活化和成肌纤维细胞分化。Thy-1对肌成纤维细胞表型的影响是广泛的,包括:降低许多肌肉特异性蛋白和肌源性转录因子的表达,抑制收缩性, 和促进细胞凋亡。此外,Thy-1的一些功能可以通过施用可溶性Thy-1来重现,并且初步数据表明可溶性Thy-1逆转小鼠模型中建立的纤维化,表明Thy-1本身可以用于或修饰以获得治疗益处。总之,这些知识使我们的整体假设,Thy-1介导的信号广泛抑制肌纤维母细胞转化,促进细胞凋亡,恢复肺成纤维细胞的稳态功能。对相关分子机制的进一步理解将揭示逆转IPF和其他纤维化疾病中致病性肌成纤维细胞表型的新策略。基于Thy-1的异质性和靶向破坏的体外和体内模型为定义成肌纤维细胞靶向策略提供了极好的机会,如以下具体目标所概述的:目标1:定义Thy-1抑制肺成纤维细胞的成肌纤维细胞分化的机制;目标2:定义Thy-1促进成肌纤维细胞凋亡的机制;以及目标3:利用Thy-1调节的信号转导在体内逆转抗骨化症的肌成纤维细胞表型。重要性:因为Thy-1调节纤维形成的多个关键信号通路,所以利用其功能比靶向其更有吸引力。 单一途径,已被证明是治疗IPF的无效方法。因此,拟议的研究将确定Thy-1抑制肺成纤维细胞促纤维化分化的机制,并将这些知识转化为纤维化肺病的创新治疗干预措施。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

James S. Hagood其他文献

Cooperative signaling between integrins and growth factor receptors in fibrosis
  • DOI:
    10.1007/s00109-020-02026-2
  • 发表时间:
    2021-01-03
  • 期刊:
  • 影响因子:
    4.200
  • 作者:
    Horacio Maldonado;James S. Hagood
  • 通讯作者:
    James S. Hagood

James S. Hagood的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('James S. Hagood', 18)}}的其他基金

KULMAP: Human Kidney, urinary tract and lung mapping center
KULMAP:人类肾脏、泌尿道和肺部绘图中心
  • 批准号:
    9987373
  • 财政年份:
    2019
  • 资助金额:
    $ 36.63万
  • 项目类别:
KULMAP: Human Kidney, urinary tract and lung mapping center
KULMAP:人类肾脏、泌尿道和肺部绘图中心
  • 批准号:
    10413576
  • 财政年份:
    2018
  • 资助金额:
    $ 36.63万
  • 项目类别:
Organ Specific Project
器官特定项目
  • 批准号:
    10237125
  • 财政年份:
    2018
  • 资助金额:
    $ 36.63万
  • 项目类别:
KULMAP: Human Kidney, urinary tract and lung mapping center
KULMAP:人类肾脏、泌尿道和肺部绘图中心
  • 批准号:
    10237122
  • 财政年份:
    2018
  • 资助金额:
    $ 36.63万
  • 项目类别:
KULMAP: Human Kidney, urinary tract and lung mapping center
KULMAP:人类肾脏、泌尿道和肺部绘图中心
  • 批准号:
    9791201
  • 财政年份:
    2018
  • 资助金额:
    $ 36.63万
  • 项目类别:
Targeting the Apoptosis-Resistant Pulmonary Myofibroblast
靶向抗凋亡肺肌成纤维细胞
  • 批准号:
    8677065
  • 财政年份:
    2012
  • 资助金额:
    $ 36.63万
  • 项目类别:
Childhood Interstitial & Diffuse Lung Disease Scientific Conference
童年插页式
  • 批准号:
    8319294
  • 财政年份:
    2012
  • 资助金额:
    $ 36.63万
  • 项目类别:
Targeting the Apoptosis-Resistant Pulmonary Myofibroblast
靶向抗凋亡肺肌成纤维细胞
  • 批准号:
    8371194
  • 财政年份:
    2012
  • 资助金额:
    $ 36.63万
  • 项目类别:
Epigenetic Alterations in IPF Fibroblastic Foci
IPF 成纤维细胞灶的表观遗传改变
  • 批准号:
    7712750
  • 财政年份:
    2009
  • 资助金额:
    $ 36.63万
  • 项目类别:
Regulation of Fibroblast Phenotype in Lung Fibrosis
肺纤维化中成纤维细胞表型的调节
  • 批准号:
    7824718
  • 财政年份:
    2009
  • 资助金额:
    $ 36.63万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 36.63万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了