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.
Chronic itch associated with dermatitis and systemic diseases is a substantial clinical problem that is poorly treated. Warmed skin is the most commonly reported factor that exacerbates itch. This project will investigate neural mechanisms of itch and its enhancement by warming, and thereby identify molecular and cellular targets for the development of novel treatments for itch.
|Sakai, Kent; Sanders, Kristen M; Youssef, Marina R et al. (2017) Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis. Pain 158:2196-2202|
|Sakai, Kent; Sanders, Kristen M; Youssef, Marina R et al. (2016) Mouse model of imiquimod-induced psoriatic itch. Pain 157:2536-2543|
|Akiyama, Tasuku; Ivanov, Margaret; Nagamine, Masaki et al. (2016) Involvement of TRPV4 in Serotonin-Evoked Scratching. J Invest Dermatol 136:154-60|
|Akiyama, Tasuku; Curtis, Eric; Nguyen, Tony et al. (2016) Anatomical evidence of pruriceptive trigeminothalamic and trigeminoparabrachial projection neurons in mice. J Comp Neurol 524:244-56|
|Carstens, Earl; Akiyama, Tasuku (2016) Central Mechanisms of Itch. Curr Probl Dermatol 50:11-7|
|Akiyama, Tasuku; Lerner, Ethan A; Carstens, E (2015) Protease-activated receptors and itch. Handb Exp Pharmacol 226:219-35|
|Akiyama, Tasuku; Nguyen, Tony; Curtis, Eric et al. (2015) A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. Pain 156:1240-6|
|Akiyama, Tasuku; Ivanov, Margaret; Nagamine, Masaki et al. (2015) Involvement of TRPV4 in serotonin-evoked scratching. J Invest Dermatol :|
|Akiyama, T; Nagamine, M; Davoodi, A et al. (2015) Intradermal endothelin-1 excites bombesin-responsive superficial dorsal horn neurons in the mouse. J Neurophysiol 114:2528-34|
|Akiyama, Tasuku; Tominaga, Mitsutoshi; Takamori, Kenji et al. (2014) Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. Pain 155:80-92|
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