Sustained signaling for fibroblast migration

描述（由申请人提供）：细胞迁移是一个基本的生物学过程，在广泛的生物和生理过程中起着重要作用。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的动力学，我们假设除了急性的信号事件外，可能还需要持续的信号事件来支持它们的缓慢迁移，并随后确定了一个持续的信号通路，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- alpha - erk途径，转录上调泛素E3连接酶RFFL的表达，该酶多泛素化并破坏PRR5L， PRR5L是PKC疏水基序列（HM）被mTORC2（哺乳动物雷帕霉素复合物2的靶标）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。这一途径不仅对成纤维细胞的体外迁移很重要，而且在小鼠模型的肺纤维化发展中似乎也起着关键作用。在这项研究中，我们将研究PKC持续激活下游调控细胞迁移的信号机制。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是一个终端，其中lpa诱导的成纤维细胞迁移起着重要作用

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.