Influence of Voltage Gated Sodium Channels on Cellular Motility and Inflammation

最近的研究表明，电压门控钠（Nav）通道除了产生和传播动作电位外，还具有生理和发育作用。例如，我们发现缺失Nav1.6亚型的幼年小鼠的视网膜电图显示出严重的异常，无法用其典型作用来解释。此外，在非兴奋性细胞如神经胶质细胞、免疫细胞和肿瘤细胞中发现了各种Nav通道同种型，它们似乎调节运输、内吞作用、分化和运动性的方面。我的计划的首要主题围绕着VGSC的新角色的发现，并确定他们发挥影响力的机制，以及解决相关问题的新工具的开发。我们知道，广泛的重塑发生在眼睛睁开后，并依赖于视觉体验。光感受器在第一次视觉体验后的几天内迅速成熟，但视网膜发育的这一方面受到的关注相对较少。我们已经发现，在第一次视觉体验之后的一段时间内，Nav通道间接调节光感受器对光的敏感程度。被称为神经营养因子的扩散性分子从视网膜内层的神经元和神经胶质细胞释放以调节感光器功能。我们认为，导航通道有助于运输和神经营养因子的释放，我建议详细研究这些过程中的视神经。我们最近发现，在两种炎症模型（神经炎症和全身性炎症）中，具有低水平通道Nav1.6的小鼠产生促炎细胞因子IL-6水平降低，活化中性粒细胞的释放减少-免疫系统的第一道防线-响应于模拟细菌感染的刺激。因此，我建议详细研究Nav1.6和其他Nav通道如何调节中性粒细胞功能。最后，在已知的十种导航通道类型中，单个导航通道类型的功能很难评估，因为用于研究它们的药物区分能力很差。我们最近使用了一种新的方法，通过使用抗体以高精度阻断个别类型的Nav通道的功能。我们建议进一步表征这些抗体，以帮助我们解决上述目标，并提供离子通道研究社区的新工具，调查钠通道。这些基本发现将为发展有利于加拿大人的创新奠定基础。例如，了解神经营养素的运输和释放是如何通过Nav通道调节的，这对我们理解视网膜变性具有重要意义。最后，该计划将使下一代加拿大神经科学家的培训在一个丰富的多学科环境。

Recent studies demonstrate that voltage--gated sodium (Nav) channels have physiological and developmental roles beyond the generation and propagation of action potentials. For example, we have found that the electroretinogram of young mice missing the Nav1.6 isoform displays profound abnormalities that cannot be explained in the context of its canonical role. In addition, various Nav channel isoforms have been found in non-excitable cells such as glia, immune cells, and neoplastic cells where they appear to regulate aspects of trafficking, endocytosis, differentiation and motility. The overarching theme of my program revolves around the discovery of new roles for VGSCs and determining the mechanism by which they exert their influence, as well as the development of new tool to address related questions. We know that extensive remodeling occurs after eye opening and is dependent on visual experience. Photoreceptors mature quickly in the days following the first visual experiences but this aspect of retinal development has received relatively little attention. We have discovered that Nav channels indirectly regulate how sensitive photoreceptors are to light during a period that follows the first visual experiences. Diffusible molecules, called neurotrophins, are released from neurons of the inner retina and glial cells to regulate photoreceptor function. We believe that Nav channels contribute to the transport and release of neurotrophins and I propose to study these processes in detail in the optic nerve. We have recently discovered that mice with low levels of the channel Nav1.6 produce reduced levels of the pro-inflammatory cytokine IL-6 in two models of inflammation (neuro-inflammation and systemic inflammation), with decreased release of activated neutrophils - the first line of defense of the immune system - in response to a stimulus which mimics a bacterial infection. I therefore propose to study in detail how Nav1.6 and other Nav channels regulate neutrophil function. Finally, the function of individual Nav channel types, among the ten that are known, has been difficult to assess because the drugs used to study them discriminate poorly. We have recently used a novel approach to block the function of individual types of Nav channels with high precision by using antibodies. We propose to further characterize these antibodies to help us address the above objectives and to provide the ion channel research community new tools to investigate sodium channels. These fundamental discoveries will establish foundations upon which innovations that benefit Canadians can be developed. For example, understanding how neurotophin transport and release is modulated by Nav channels has implications for our understanding of retinal degenerations. Finally, this program will enable the training of the next generation of Canadian neuroscientists in a rich multidisciplinary environment.