Warmth enhancement of itch via TRPV4

通过 TRPV4 温暖增强瘙痒

• 批准号: 8816308
• 负责人: Tasuku Akiyama
• 金额: $ 24.9万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816308
• 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; receptor; response; species difference; tool

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，为新世纪的发展做出贡献 减轻瘙痒和疼痛的治疗，以对这些感觉背后的机制的新知识为指导。 到目前为止，我学习了各种分子生物学方法，获得了广泛的行为学培训 评估啮齿动物的疼痛和瘙痒，并获得了使用体内电生理学和 细胞成像方法，以研究瘙痒的机制在YKuraishi教授和E。 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 神经解剖学和人类心理物理方法，我认为这些方法对我的职业发展至关重要。 特别是，我认为至关重要的是要解决是否在 啮齿动物在人类中受到保护，以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系列研讨会中任教，这是我职业生涯中有价值的组成部分 学术界的发展与K99/R00奖励机制的目标一致。《纽约时报》 系和更大的加州大学戴维斯分校拥有许多国际公认的神经科学教员， 提供优秀的智力环境，对我的职业发展产生了积极的影响。 因此，我相信我的背景和在支持性研究环境中的培训使我成为一个高度 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。 治疗，显著降低了生活质量。皮肤变暖是最常见的报告因素 会加剧瘙痒。更好地理解变暖增强瘙痒的潜在机制是 迫切需要确定细胞靶点，以开发新的止痒疗法。这项提议将 采取多学科方法，使用药理学和遗传学工具，并结合行为学 评估，钙成像和感觉神经元免疫组织化学，电生理记录，以及 人类心理物理学研究无害皮肤引起瘙痒的潜在机制 变暖了。在分子水平上，温度感觉涉及到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。用抓挠作为啮齿类动物 瘙痒模型，我们的初步数据显示，5-羟色胺引起的抓挠需要TRPV4并得到增强 通过变暖。这一提议的中心假设是，TRPV4是增强5-羟色胺所必需的。 因变暖而引起的瘙痒。 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 结合遗传学方法研究TRPV4在瘙痒中的作用以及通过 无伤大雅的变暖。