Sustained signaling for fibroblast migration
成纤维细胞迁移的持续信号传导
基本信息
- 批准号:9066227
- 负责人:
- 金额:$ 41.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-01 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdaptor Signaling ProteinAttenuatedBackBindingBinding ProteinsBiologicalBiological ProcessBleomycinCell PolarityCellsChemotactic FactorsComplexDevelopmentDiseaseEndosomesEventFRAP1 geneFibroblastsFibrosisG-Protein-Coupled ReceptorsGoalsGolgi ApparatusHamman-Rich syndromeHealthHourIn VitroKineticsLeadLengthLungMediatingMicrotubulesModelingMorbidity - disease rateMusPathway interactionsPhosphorylationPhysiologicalPhysiological ProcessesPlayProcessProtein KinaseProteomicsPulmonary FibrosisRecyclingRefractoryRegulationRoleSignal PathwaySignal TransductionTerminal DiseaseTestingTherapeuticTherapeutic InterventionTimebasecell motilityeffective therapyin vivoinhibitor/antagonistinnovationinsightlysophosphatidic acidmTOR inhibitionmigrationmortalitymouse modelneutrophilnovelnovel therapeutic interventionphase III trialresearch studyruboxistaurintherapeutic targetubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): Cell migration is a fundamental biological process that plays an important role in a wide range of biological and physiological processes. Its deregulation causes or contributes too many diseases, including pulmonary fibrosis. Based on the kinetics of fibroblast migration, we hypothesized that sustained signaling events, in addition to the acute ones, may be needed to support their slow-pace migration and subsequently identified one of the sustained signaling pathways as being critically important for LPA-induced fibroblast migration. In this pathway, LPA acts, through a G¿12-ARAF-ERK pathway, to transcriptionally upregulate the expression of an ubiquitin E3 ligase RFFL, which polyubiquitinates and destabilizes PRR5L, a specific inhibitor of PKC hydrophobic motif (HM) phosphorylation by mTORC2 (Mammalian target of rapamycin complex 2). The elimination of RFFL leads to sustained PKC HM phosphorylation and activation. This pathway is not only important for fibroblast migration in vitro, also appears to have a key role in pulmonary fibrosis development in a mouse model. In this study, we will investigate the signaling mechanisms downstream of the sustained PKC activation for the regulation of cell migration. We will also validate the importance of this sustained signaling pathway for cell migration in vivo and evaluate the therapeutic potential of a PKC inhibitor in a mouse model of idiopathic pulmonary fibrosis (IPF). IPF, in which LPA-induced fibroblast migration has an important role, is a terminal
disease with no effective treatments.
描述(由申请人提供):细胞迁移是一个基本的生物过程,在广泛的生物和生理过程中发挥着重要作用。它的放松管制导致或促成了太多的疾病,包括肺纤维化。基于成纤维细胞迁移动力学,我们假设除了急性信号事件外,可能还需要持续信号事件来支持其慢速迁移,并随后确定了持续信号通路之一对于 LPA 诱导的成纤维细胞迁移至关重要。在此通路中,LPA 通过 G¿12-ARAF-ERK 通路,在转录上上调泛素 E3 连接酶 RFFL 的表达,该酶使 PRR5L 多泛素化并使其不稳定,PRR5L 是 mTORC2(雷帕霉素复合物 2 的哺乳动物靶标)对 PKC 疏水基序 (HM) 磷酸化的特异性抑制剂。 RFFL 的消除导致 PKC HM 持续磷酸化和激活。该途径不仅对体外成纤维细胞迁移很重要,而且似乎在小鼠模型的肺纤维化发展中也具有关键作用。在本研究中,我们将研究 PKC 持续激活下游的信号传导机制,以调节细胞迁移。我们还将验证这种持续信号通路对体内细胞迁移的重要性,并评估 PKC 抑制剂在特发性肺纤维化 (IPF) 小鼠模型中的治疗潜力。 IPF是一种终末期的疾病,LPA诱导的成纤维细胞迁移在其中发挥着重要作用。
没有有效治疗方法的疾病。
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)
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Dianqing Wu其他文献
Dianqing Wu的其他文献
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{{ truncateString('Dianqing Wu', 18)}}的其他基金
Signaling mechanisms and functions related to patho-physiology of vascular, lung and blood systems
与血管、肺和血液系统病理生理学相关的信号传导机制和功能
- 批准号:
9244290 - 财政年份:2017
- 资助金额:
$ 41.63万 - 项目类别:
DKK2 regulates NK activation and tumor immunity
DKK2 调节 NK 激活和肿瘤免疫
- 批准号:
10064071 - 财政年份:2017
- 资助金额:
$ 41.63万 - 项目类别:
Signaling mechanisms and functions related to patho-physiology of vascular, lung and blood systems
与血管、肺和血液系统病理生理学相关的信号传导机制和功能
- 批准号:
10570974 - 财政年份:2017
- 资助金额:
$ 41.63万 - 项目类别:
DKK2 regulates NK activation and tumor immunity
DKK2 调节 NK 激活和肿瘤免疫
- 批准号:
10307994 - 财政年份:2017
- 资助金额:
$ 41.63万 - 项目类别:
Signaling mechanisms and functions related to patho-physiology of vascular, lung and blood systems
与血管、肺和血液系统病理生理学相关的信号传导机制和功能
- 批准号:
10089468 - 财政年份:2017
- 资助金额:
$ 41.63万 - 项目类别:
Identification of novel genes as being important for neutrophil functions
鉴定对中性粒细胞功能重要的新基因
- 批准号:
8415495 - 财政年份:2012
- 资助金额:
$ 41.63万 - 项目类别: