Warmth enhancement of itch via TRPV4

通过 TRPV4 温暖增强瘙痒

• 批准号: 8509420
• 负责人: Tasuku Akiyama
• 金额: $ 8.79万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509420
• 关键词: 4-nitrophenethyl bromide; Academia; Address; Afferent Neurons; Agonist; Antipruritics; Atopic Dermatitis; Award; Behavior; Behavior assessment; Calcium; Chemicals; Chronic; Clinical; Coupled; Data; Dermatitis; Development; Educational process of instructing; Electrophysiology (science); Environment; Esthesia; Faculty; G-Protein-Coupled Receptors; Genetic; Goals; Histamine; Housing; Human; Image; Immunohistochemistry; Ion Channel; Knockout Mice; Knowledge; Learning; Mediating; Mediator of activation protein; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Biology; Molecular Target; Mus; Neurons; Neurosciences; Pain; Psychophysics; Quality of life; Reporting; Research; Research Personnel; Research Project Grants; Rodent; Rodent Model; Role; Series; Serotonin; Signal Pathway; Signal Transduction; Skin; Spinal Cord; Spinal Ganglia; Systemic disease; TRPV1 gene; Temperature; Testing; Training; base; career; career development; cellular imaging; cellular targeting; experience; ganglion cell; imaging modality; in vivo; interdisciplinary approach; neuromechanism; novel; programs; public health relevance; receptor; response; species difference; tool

DESCRIPTION (provided by applicant): My career goal is to become an independent academic researcher and to contribute to the development of new treatments for relief of itch and pain, guided by new knowledge of the mechanisms underlying these sensations. To date, I learned a variety of molecular biology methods, obtained extensive training in the behavioral assessment of pain and itch in rodents, and gained extensive experience using in vivo electrophysiology and cellular imaging methods to investigate itch mechanisms under the mentorship of Prof. Y. Kuraishi and Prof. E. Carstens. Through the research project described below, I will acquire additional training in these and other neuroanatomical and human psychophysical approaches that I consider essential to my career development. In particular, I believe it is essential to address whether the novel neuronal mechanisms of itch identified in rodents are conserved in humans, in order to develop new mechanisms-based strategies to treat itch and pain. Additionally, I will teach in established courses and seminar series, a valuable component of my career development in academia that is consistent with the goals of the K99/R00 award mechanism. The NPB department and larger UC Davis campus houses many internationally-recognized neuroscience faculty, providing an outstanding intellectual environment that has positively influenced my career development. Therefore, I believe that my background and training in a supportive research environment make me a highly appropriate candidate for the K99/R00 award. Chronic itch associated with dermatitis and systemic diseases is a substantial clinical problem that is poorly treated, significantly decreasing the quality of lfe. Warmed skin is the most commonly reported factor that exacerbates itch. A better understanding of mechanisms underlying enhancement of itch by warming is urgently needed to identify cellular targets for development of novel antipruritic treatments. This proposal will takea multidisciplinary approach, using pharmacological and genetic tools combined with behavioral assessment, calcium imaging and immunohistochemistry of sensory neurons, electrophysiology recording, and human psychophysics to investigate mechanisms underlying the enhancement of itch by innocuous skin warming. At the molecular level, temperature sensation involves thermosensitive transient receptor potential (TRP) ion channels. One of these, TRPV4, is activated by innocuous warmth. Using scratching as a rodent model of itch, our preliminary data show that scratching elicited by serotonin requires TRPV4 and is enhanced by warming. The central hypothesis of this proposal is that TRPV4 is required for enhancement of serotonin- evoked itch by warming. The present proposal represents a departure from the research program of my mentor, Prof. Carstens, by incorporating genetic approaches to investigate the role of TRPV4 in itch and the modulation of itch by innocuous warming.

描述(申请人提供)：我的职业目标是成为一名独立的学术研究人员，并在对这些感觉背后的机制的新知识的指导下，为缓解瘙痒和疼痛的新疗法的开发做出贡献。到目前为止，我学习了各种分子生物学方法，在啮齿动物疼痛和瘙痒的行为评估方面获得了广泛的培训，并在Y.Kuraishi教授和E.Carstens教授的指导下，获得了使用体内电生理学和细胞成像方法研究瘙痒机制的丰富经验。通过下面描述的研究项目，我将在这些和其他我认为对我的职业发展至关重要的神经解剖学和人类心理物理学方法方面获得额外的培训。特别是，我认为必须解决在啮齿类动物中发现的新的神经元瘙痒机制是否在人类中保守，以便开发基于机制的新策略来治疗瘙痒和疼痛。此外，我将在既定的课程和研讨会系列中任教，这是我在学术界职业发展的宝贵组成部分，与K99/R00奖励机制的目标一致。NPB系和加州大学戴维斯分校更大的校区拥有许多国际公认的神经科学教师，提供了一个出色的智力环境，对我的职业发展产生了积极的影响。因此，我相信我的背景和在支持性研究环境中的培训使我成为K99/R00奖的非常合适的候选人。与皮炎和全身疾病相关的慢性瘙痒是一个严重的临床问题，治疗不当，显著降低了LFE的质量。温暖的皮肤是最常见的加剧瘙痒的因素。迫切需要更好地了解变暖增强瘙痒的潜在机制，以确定开发新的止痒治疗的细胞靶点。这项建议将采取多学科的方法，结合行为评估、钙成像和感觉神经元的免疫组织化学、电生理学记录和人类心理物理学，使用药理学和遗传学工具来研究无害的皮肤加温增强瘙痒的潜在机制。在分子水平上，温度感觉涉及温度敏感的瞬时受体电位(Trp)离子通道。其中之一，TRPV4，是由无害的温暖激活的。使用抓挠作为啮齿类动物的瘙痒模型，我们的初步数据显示，由5-羟色胺引发的抓挠需要TRPV4，并因变暖而增强。这一建议的中心假设是，TRPV4是通过升温增强5-羟色胺引起的瘙痒所必需的。目前的建议与我的导师卡斯滕斯教授的研究计划背道而驰，通过结合遗传学方法来研究TRPV4在瘙痒中的作用以及无害的升温对瘙痒的调节。