Sustained signaling for fibroblast migration

描述（由申请人提供）：细胞迁移是一种基本的生物学过程，在广泛的生物学和生理学过程中发挥重要作用。它的失调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，可能需要持续的信号传导事件，以支持他们的慢节奏迁移，并随后确定了持续的信号传导途径之一是至关重要的LPA诱导的成纤维细胞迁移。在该途径中，LPA通过G12-ARAF-ERK途径转录上调泛素E3连接酶RFFL的表达，RFFL使PRR 5L聚泛素化并使PRR 5L不稳定，PRR 5L是mTORC 2（雷帕霉素复合物2的哺乳动物靶点）对PKC疏水基序（HM）磷酸化的特异性抑制剂。RFFL的消除导致持续的PKC HM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中的肺纤维化发展中具有关键作用。在这项研究中，我们将探讨下游的持续PKC激活的细胞迁移的调节信号机制。我们还将验证这种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是一种终末疾病，其中LPA诱导的成纤维细胞迁移具有重要作用， 没有有效治疗的疾病。

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.