Warmth enhancement of itch via TRPV4

通过 TRPV4 温暖增强瘙痒

• 批准号: 9464077
• 负责人: Tasuku Akiyama
• 金额: $ 7.79万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9464077
• 关键词: Warmth; enhancement; itch; via; TRPV4

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 life. 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 take a 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.

我的职业目标是成为一名独立的学术研究员并为新学科的发展做出贡献 以这些感觉背后机制的新知识为指导，进行缓解瘙痒和疼痛的治疗。 迄今为止，我学习了多种分子生物学方法，获得了行为学方面的广泛培训 评估啮齿类动物的疼痛和瘙痒，并利用体内电生理学和方法获得了丰富的经验 在 Y. Kuraishi 教授和 E. E. 教授的指导下，利用细胞成像方法研究瘙痒机制。 卡斯滕斯。通过下面描述的研究项目，我将获得这些和其他方面的额外培训 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。 特别是，我认为有必要解决是否在中发现的瘙痒的新神经元机制 啮齿动物在人类中得到保护，以便开发新的基于机制的策略来治疗瘙痒和疼痛。 此外，我将教授既定课程和研讨会系列，这是我职业生涯的宝贵组成部分 学术界的发展与K99/R00奖励机制的目标一致。国家政策委员会 系和更大的加州大学戴维斯分校校园拥有许多国际认可的神经科学教师， 提供了一个优秀的智力环境，对我的职业发展产生了积极的影响。 因此，我相信我的背景和支持性研究环境中的培训使我成为一名高度 K99/R00 奖的合适候选人。 与皮炎和全身性疾病相关的慢性瘙痒是一个严重的临床问题，但目前尚未得到很好的解决。 治疗，显着降低生活质量。皮肤变暖是最常见的报告因素 加剧瘙痒。更好地理解变暖加剧瘙痒的机制是 迫切需要确定细胞靶点以开发新型止痒疗法。该提案将 采取多学科方法，利用药理学和遗传学工具结合行为学 评估、感觉神经元的钙成像和免疫组织化学、电生理学记录以及 人类心理物理学研究无害皮肤增强瘙痒的机制 变暖。在分子水平上，温度感觉涉及热敏瞬时受体电位 (TRP) 离子通道。其中之一，TRPV4，是由无害的温暖激活的。像啮齿动物一样使用抓挠 瘙痒模型，我们的初步数据表明，血清素引起的抓挠需要 TRPV4，并且会增强 通过变暖。该提案的中心假设是 TRPV4 是增强血清素所必需的。 因升温而引起瘙痒。 目前的提案与我的导师卡斯滕斯教授的研究计划背道而驰。 结合遗传方法来研究 TRPV4 在瘙痒中的作用以及通过以下方式调节瘙痒 无害的变暖。