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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：
Dianqing Wu
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
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：
https://reporter.nih.gov/project-details/9066227
关键词：
Acute Adaptor Signaling Protein Attenuated Back Binding Binding Proteins Biological Biological Process Bleomycin Cell Polarity Cells Chemotactic Factors Complex Development Disease Endosomes Event FRAP1 gene Fibroblasts Fibrosis G-Protein-Coupled Receptors Goals Golgi Apparatus Hamman-Rich syndrome Health Hour In Vitro Kinetics Lead Length Lung Mediating Microtubules Modeling Morbidity - disease rate Mus Pathway interactions Phosphorylation Physiological Physiological Processes Play Process Protein Kinase Proteomics Pulmonary Fibrosis Recycling Refractory Regulation Role Signal Pathway Signal Transduction Terminal Disease Testing Therapeutic Therapeutic Intervention Time base cell motility effective therapy in vivo inhibitor/antagonist innovation insight lysophosphatidic acid mTOR inhibition migration mortality mouse model neutrophil novel novel therapeutic intervention phase III trial research study ruboxistaurin therapeutic target ubiquitin-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。