Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury
靶向 ABL 激酶调节损伤后上皮细胞可塑性和再生
基本信息
- 批准号:10666351
- 负责人:
- 金额:$ 49.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcuteAcute Lung InjuryAirAlveolarAlveolar CellArchitectureBacterial InfectionsBacterial PneumoniaBasal CellBiochemicalBiological AssayCell ProliferationCellsClinical effectivenessCoculture TechniquesComplementCoupledDNA DamageDataDifferentiation AntigensEpithelial Cell ProliferationEpithelial CellsEpitheliumGeneticHIF1A geneHypoxiaHypoxia Inducible FactorInflammationInjuryLiquid substanceLungLung AdenocarcinomaLung NeoplasmsMediatingModelingMusNatural regenerationNatureOrganoidsPathologicPathway interactionsPhosphotransferasesPlayPopulationPredispositionRegulationReportingResidual stateRoleSignal PathwaySignal TransductionSignaling MoleculeSolid NeoplasmStimulusStressTimeTissuesTranscription CoactivatorTyrosine Phosphorylationairway epitheliumairway regenerationalveolar epitheliumbronchial epitheliumcell injurycell motilitycell regenerationcell typechemotherapyeffectiveness evaluationepithelial stem cellepithelium regenerationin vivoinhibitorinjured airwayinjury and repairinsightleukemialoss of functionlung regenerationmouse modelnovelpathogenpharmacologicpneumonia modelprogenitorregeneration following injuryrepairedresponseresponse to injurystem cell proliferationstem cellstherapeutic targettranscription factortumortumorigenesis
项目摘要
ABSTRACT
Tyrosine phosphorylation networks have been implicated in the regulation of epithelial cell plasticity, which is
often induced by injury in multiple tissue types. Regeneration following injury is mediated by dynamic
intercellular signaling among diverse epithelial progenitor cell populations and residual cells. Recent studies
have revealed a significant role for cell plasticity mechanisms induced by injury where cells from one region
contribute to repair of another region after severe and acute damage. Despite the identification of multiple
region-specific progenitor cells activated following injury, the identity of molecules that might be therapeutically
targeted in response to injury to promote activation of progenitor cell types has remained elusive. We recently
showed that Abl kinases are highly activated in bronchial epithelial cells in response to pathogen-induced injury,
and that Abl inactivation in a subpopulation of airway cells promotes intercellular signaling among lung epithelial
cell progenitors to induce alveolar regeneration after bacterial pneumonia challenge. Further, we have recently
found that inhibition of Abl kinases after airway damage induced by toxic agents (SO2 exposure) promotes
basal cell proliferation and enhances differentiation. Together these data reveal for the first time a role for Abl
kinases in regeneration of both the alveolar and airway epithelium after injury by pathogens and toxic agents.
The overall hypothesis is that activation of the Abl kinases in response to injury promotes lung epithelial
damage, and that Abl inactivation in lung epithelial progenitors promotes efficient and rapid regeneration and
re-establishment of tissue architecture following injury. The specific aims are: 1. Evaluate the role of Abl kinases
in the regulation of alveolar epithelium regeneration in response to pathogen-induced injury. To this end we
will: A) evaluate the role of Abl kinases in alveolar regeneration in response to acute lung injury and assess
the effectiveness of Abl inhibitors to enhance both residual progenitor cell proliferation as well as invoking
plasticity of airway progenitors for efficient and rapid alveolar regeneration; and B) assess whether Abl1 targets
the HIF1 transcription factor in response to alveolar injury and repair. 2. Define the Abl-dependent pathways
implicated in airway epithelium regeneration. In this aim, we will A) evaluate whether Abl kinases modulate the
response of the airway epithelium during injury and whether Abl inactivation functions to promote airway
regeneration required to restore airway epithelial architecture and function; and B) identify Abl-regulated
pathways altered in the regenerating airway epithelium and evaluate the role of selected Abl targets including
Yap1 in the regulation of airway epithelial cell proliferation, differentiation, and survival after injury. These
studies break new ground as they will define novel Abl-regulated pathways activated in response to injury and
identify epithelial progenitors with enhanced cell plasticity in response to Abl inactivation, leading to
regeneration of the lung epithelium.
摘要
酪氨酸磷酸化网络与上皮细胞可塑性的调节有关,
通常由多种组织类型的损伤引起。损伤后的再生由动力介导
不同上皮祖细胞群体和残余细胞之间的细胞间信号传导。最近的研究
已经揭示了损伤诱导的细胞可塑性机制的重要作用,其中来自一个区域的细胞
有助于在严重和急性损伤后修复另一个区域。尽管发现了多个
损伤后激活的区域特异性祖细胞,可能是治疗性的分子的身份,
靶向响应损伤以促进祖细胞类型的活化仍然是难以捉摸的。我们最近
显示Abl激酶在支气管上皮细胞中响应于病原体诱导的损伤而高度活化,
并且Abl在气道细胞亚群中的失活促进肺上皮细胞之间的细胞间信号传导,
细胞祖细胞诱导细菌性肺炎攻击后的肺泡再生。此外,我们最近
发现在毒性试剂(SO2暴露)诱导的气道损伤后抑制Abl激酶促进了
基底细胞增殖并增强分化。这些数据首次揭示了Abl的作用,
激酶在病原体和毒剂损伤后肺泡和气道上皮细胞再生中的作用。
总的假设是,响应于损伤的Abl激酶的激活促进肺上皮细胞的增殖。
肺上皮祖细胞中的Abl失活促进有效和快速的再生,
损伤后组织结构的重建。具体目标是:1.评估Abl激酶的作用
在调节肺泡上皮再生的病原体诱导的损伤。为此我们
A)评估Abl激酶在响应急性肺损伤的肺泡再生中的作用,
Abl抑制剂增强残余祖细胞增殖以及激活
气道祖细胞对于有效和快速肺泡再生的可塑性;和B)评估BMP 1是否靶向
HIF 1 α转录因子对肺泡损伤和修复的反应。2.定义依赖于神经元的通路
与气道上皮再生有关。在这个目标中,我们将A)评估Abl激酶是否调节
在损伤期间气道上皮的反应以及Abl失活是否起到促进气道上皮的作用。
B)鉴定呼吸道上皮结构和功能恢复所需的再生;和
再生气道上皮细胞中改变的通路,并评估所选Abl靶点的作用,包括
Yap 1在损伤后气道上皮细胞增殖、分化和存活中的调节作用。这些
研究开辟了新的领域,因为它们将定义响应损伤而激活的新的β-调节途径,
鉴定响应Abl失活具有增强的细胞可塑性的上皮祖细胞,导致
肺上皮的再生。
项目成果
期刊论文数量(0)
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Ann Marie Pendergast其他文献
Ann Marie Pendergast的其他文献
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{{ truncateString('Ann Marie Pendergast', 18)}}的其他基金
Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis
靶向肿瘤-神经细胞相互作用抑制肺癌脑转移
- 批准号:
10164550 - 财政年份:2021
- 资助金额:
$ 49.56万 - 项目类别:
Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis
靶向肿瘤-神经细胞相互作用抑制肺癌脑转移
- 批准号:
10581652 - 财政年份:2021
- 资助金额:
$ 49.56万 - 项目类别:
Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis
靶向肿瘤-神经细胞相互作用抑制肺癌脑转移
- 批准号:
10366021 - 财政年份:2021
- 资助金额:
$ 49.56万 - 项目类别:
Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury
靶向 ABL 激酶调节损伤后上皮细胞可塑性和再生
- 批准号:
10396637 - 财政年份:2020
- 资助金额:
$ 49.56万 - 项目类别:
Novel target for therapy refractory lung tumors
治疗难治性肺部肿瘤的新靶点
- 批准号:
9269186 - 财政年份:2015
- 资助金额:
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Novel target for therapy refractory lung tumors
治疗难治性肺部肿瘤的新靶点
- 批准号:
9065535 - 财政年份:2015
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Novel target for therapy refractory lung tumors
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Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
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Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
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Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
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- 批准号:
8199099 - 财政年份:2011
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