Sustained signaling for fibroblast migration

描述(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扮演着重要的角色。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的动力学，我们假设除了急性信号事件外，可能还需要持续的信号事件来支持它们的慢速迁移，并随后发现其中一条持续的信号通路对LPA诱导的成纤维细胞迁移至关重要。在这一途径中，LPA通过G？12-ARAF-ERK途径在转录上上调泛素E3连接酶RFFL的表达，泛素E3连接酶RFFL可泛素化并破坏PRR5L的稳定，PRR5L是mTORC2(雷帕霉素复合体2的哺乳动物靶标)对PKC疏水基序(HM)磷酸化的特异性抑制物。RFFL的消除导致PKC HM持续的磷酸化和激活。这一途径不仅对成纤维细胞在体外的迁移很重要，而且在小鼠模型的肺纤维化发展过程中似乎也起着关键作用。在这项研究中，我们将研究持续的PKC激活下游的信号机制来调节细胞迁移。我们还将验证这一持续的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在LPA诱导的成纤维细胞迁移中起着重要作用，是一种终末 没有有效治疗方法的疾病。

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.