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：
8707850
负责人：
Dianqing Wu
金额：
$ 40.79万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707850
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 Fibroblasts Fibrosis G-Protein-Coupled Receptors Goals Golgi Apparatus Hamman-Rich syndrome Hour In Vitro Kinetics Lead Length Lung Lysophospholipids Mediating Microtubules Modeling Morbidity - disease rate Mus Pathway interactions Phase III Clinical Trials 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 mTOR protein migration mortality mouse model neuronal cell body neutrophil novel novel therapeutics public health relevance 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）：细胞迁移是一种基本的生物过程，在广泛的生物和生理过程中发挥着重要作用，其失调会导致或促成许多疾病，包括肺纤维化。我们发现，除了急性信号事件之外，可能还需要持续的信号事件来支持它们的慢速迁移，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。 LPA 通过 G¿ 12-ARAF-ERK 通路，转录上调泛素 E3 连接酶 RFFL 的表达，使 PRR5L 多聚泛素化并使其不稳定，PRR5L 是 mTORC2（雷帕霉素复合物 2 的哺乳动物靶点）磷酸化 PKC 疏水基序 (HM) 的特异性抑制剂。 RFFL 导致持续的 PKC HM 磷酸化和激活。该途径不仅对于重要。体外成纤维细胞迁移似乎也在小鼠模型中的肺纤维化发展中发挥关键作用。在这项研究中，我们将研究持续 PKC 激活的信号下游机制对细胞迁移调节的重要性。体内细胞迁移的持续信号通路的研究，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，其中 LPA 诱导的成纤维细胞迁移发挥着重要作用。没有有效治疗方法的疾病。