Transgenic Regulation of Keratinocyte to Nociceptor Signaling

角质形成细胞对伤害感受器信号转导的转基因调控

• 批准号: 8280863
• 负责人: Michael J Caterina
• 金额: $ 21.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280863
• 关键词: Acute; Address; Adverse effects; Affect; Afferent Neurons; Agonist; Analgesics; Apical; Behavior; Behavioral; Biological Assay; Capsaicin; Cells; Chemicals; Communication; Cutaneous; Development; Dose-Limiting; Epidermis; Epithelial Cells; Event; Exhibits; FOS gene; Future; Generations; Grant; Histologic; Intervention; Ion Channel; Lead; Light; Mechanics; Mediator of activation protein; Monitor; Mus; Nervous system structure; Neurons; Nociception; Nociceptors; Outcome; Pain; Pain management; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Public Health; Receptor Activation; Regulation; Resolution; Role; Signal Transduction; Skin; Specificity; Spinal Cord; Spinal cord posterior horn; Stimulus; TRPV1 gene; Testing; Therapeutic; Therapeutic Agents; Transgenic Mice; Transgenic Organisms; arm; base; chronic pain; fighting; improved; in vivo; information processing; insight; keratinocyte; promoter; receptor; receptor expression; research study; response; selective expression; spatiotemporal; success; tool; transcription factor

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. PUBLIC HEALTH RELEVANCE: We seek to understand how non-neuronal skin cells help the nervous system detect and respond to painful environmental stimuli. A better understanding of this communication within the skin will aid the development of improved drugs to fight chronic pain that lack the unwanted side effects that limit the usefulness of currently available pain medications.

描述（由申请人提供）：慢性疼痛是一个重要的公共卫生问题，目前的治疗方法不足以解决这一问题。开发更好的疼痛治疗方法将需要更好地理解伤害性神经元被激活或抑制的基本机制。越来越多的证据表明，通过热、化学或机械刺激激活皮肤角质形成细胞可导致邻近表皮伤害感受器末端的激活或抑制，并且这种信号传导可能在基底角质形成细胞层与浅表角质形成细胞层之间表现出特异性。明确解决这些可能性的一个主要障碍是缺乏一种选择性刺激角质形成细胞而不同时刺激角质形成细胞的方法。 刺激伤害感受器在这个建议中，我们概述了一个计划，选择性地表达，在转基因小鼠角质形成细胞，离子通道受体（TRPV 1和channelrhodopsin），可以独特地激活化学和/或光刺激。在完整小鼠中激活这些受体将使我们能够确定角质形成细胞刺激是否足以触发疼痛相关行为和脊髓信号。此外，通过精确调节这些通道在离散表皮层中的表达模式，我们将能够确定角质形成细胞的信号传导的结果如何在表皮的基底到顶端光谱中不同。这些目标的成功将使我们更清楚地了解角质形成细胞在引发和控制疼痛中的作用，以及未来使我们能够指导合理开发改善疼痛疗法的新工具。 公共卫生相关性：我们试图了解非神经元皮肤细胞如何帮助神经系统检测和响应疼痛的环境刺激。更好地了解皮肤内的这种沟通将有助于开发改进的药物来对抗慢性疼痛，这些药物没有限制目前可用止痛药有效性的不必要的副作用。