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
酪氨酸磷酸化网络参与了上皮细胞可塑性的调节,即
通常是由多种组织类型的损伤引起的。损伤后的再生是由动态调节的
不同上皮祖细胞群和残留细胞之间的细胞间信号传递。最新研究
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
帮助修复严重和急性损伤后的另一个区域。尽管发现了多个
损伤后激活的区域特异性祖细胞,可能用于治疗的分子的身份
针对损伤反应以促进祖细胞类型激活的靶点仍然难以捉摸。我们最近
显示在病原体诱导的损伤反应中,支气管上皮细胞中的Abl激酶高度激活,
呼吸道细胞亚群中Abl的失活促进了肺上皮细胞间的信号转导
细菌性肺炎后细胞前体细胞诱导肺泡再生。此外,我们最近已经
发现在有毒物质(SO2暴露)诱导的呼吸道损伤后抑制Abl激酶促进
促进基底细胞增殖和分化。这些数据一起首次揭示了Abl的角色
在病原体和有毒物质损伤后,肺泡和呼吸道上皮再生中的激酶。
总的假设是,损伤反应中Abl激酶的激活促进了肺上皮细胞
肺上皮祖细胞ABL失活可促进高效、快速的再生和
损伤后组织结构的重建。具体目标是:1.评估Abl激酶的作用
在病原体诱导的损伤反应中对肺泡上皮再生的调节。为此,我们
将:a)评估Abl激酶在急性肺损伤后肺泡再生中的作用,并评估
ABL抑制剂促进残余祖细胞增殖的有效性以及激活
有效和快速再生肺泡的气道祖细胞的可塑性;以及B)评估ABL1靶点
HIF1转录因子在肺泡损伤修复中的作用2.定义Abl依赖的通路
与呼吸道上皮再生有关。在这个目标中,我们将A)评估Abl激酶是否调节
损伤时呼吸道上皮细胞的反应及Abl失活是否起促进作用
恢复呼吸道上皮结构和功能所需的再生;以及B)识别Abl调节的
在再生的呼吸道上皮中改变的通路和评估选择的Abl靶点的作用包括
YAP1在调节呼吸道上皮细胞增殖、分化和损伤后存活中的作用。这些
研究取得了新的突破,因为他们将定义新的Abl调节的通路,以响应伤害和
鉴定ABL失活后细胞可塑性增强的上皮祖细胞,导致
肺上皮细胞再生。
项目成果
期刊论文数量(0)
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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:
$ 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:
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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$ 49.56万 - 项目类别:
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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