Transgenic Regulation of Keratinocyte to Nociceptor Signaling

描述(由申请人提供)：慢性疼痛是一个重大的公共卫生问题，目前的治疗方法不够充分。改进的疼痛治疗方法的发展需要更好地理解伤害性神经元被激活或被抑制的基本机制。越来越多的证据表明，热、化学或机械刺激激活皮肤角质形成细胞可导致相邻的表皮伤害性感受器终末的激活或抑制，这种信号可能在角质形成细胞的底层和表层表现出特异性。解决这些可能性的一个主要障碍是缺乏选择性刺激角质形成细胞的手段，而不是同时 刺激伤害性感受器本身。在这个建议中，我们概述了一个计划，在转基因小鼠角质形成细胞中选择性地表达离子通道受体(TRPV1和通道视紫红质)，这些受体可以被化学和/或光刺激唯一地激活。在完好的小鼠体内激活这些受体将使我们能够确定角质形成细胞的刺激是否足以触发疼痛相关行为和脊髓信号。此外，通过精确地调控这些通道在离散的表皮层中的表达模式，我们将能够确定角质形成细胞发出的信号的后果如何在表皮的基底层到顶层光谱上有所不同。这些目标的成功将使我们更清楚地了解角质形成细胞在疼痛的启动和控制中的作用，以及未来将使我们能够指导合理发展改进的疼痛治疗的强大的新工具。

DESCRIPTION (provided by applicant): Chronic pain is a significant public health problem for which current therapies are inadequate. The development of improved treatments for pain will require a better understanding of the fundamental mechanisms by which nociceptive neurons are activated or inhibited. A growing body of evidence suggests that activation of skin keratinocytes by thermal, chemical, or mechanical stimuli could result in activation or inhibition of adjacent epidermal nocieptor terminals, and that such signaling might exhibit specificity among basal vs. superficial keratinocyte layers. A major hurdle to addressing these possibilities definitively is the lack of a means of selectively stimulating keratinocytes without simultaneously stimulating nociceptors, themselves. In this proposal, we outline a plan to selectively express, within transgenic mouse keratinocytes, ion channel receptors (TRPV1 and channelrhodopsin) that can be uniquely activated by chemical and/or light stimuli. Activation of these receptors in the intact mouse will allow us to determine whether keratinocyte stimulation is sufficient to trigger pain-related behaviors and signaling to the spinal cord. Furthermore, by precisely regulating the expression patterns of these channels in discrete epidermal layers, we will be able to establish how the consequences of signaling from keratinocytes differ across the basal to apical spectrum of the epidermis. Success in these aims will provide us with a clearer understanding of the role of keratinocytes in the initiation and control of pain, as well as powerfl new tools that will in the future allow us to guide the rational development of improved therapies for pain.