Elucidation of mechanisms underlying regulation of inflammatory cellular responses by redox-sensitive TRP channels.

• Project/Area Number: 24249017
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: Mori Yasuo 京都大学, 地球環境学堂, 教授 (80212265)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥45,630,000 (Direct Cost: ¥35,100,000、Indirect Cost: ¥10,530,000); Fiscal Year 2015: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2014: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2013: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2012: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
• Keywords: カルシウム / TRP / チャネル / レドックス / 活性酸素種 / 炎症 / 生理学 / イオンチャネル / シグナル伝達 / ストレス / 癌

Outline of Final Research Achievements

Reactive oxygen species (ROS) and electrophiles, known to exert stress on organisms, are emerging as mediators of cellular signals. Transient Receptor Potential (TRP) Ca2+-permeable cation channels are activated by various triggers from outside and inside the cell. We and others have revealed that multiple redox-sensitive TRPs sense ROS to induce diverse physiological/pathological responses, such as cell death, chemotaxis, and pain transduction. TRPs sense ROS/electrophiles either indirectly through second messengers or directly via oxidative modification of cysteine residues. In this project, I clarified roles of redox-sensitive TRPs in inflammation. In particular, TRPM2 turned out to be a key signal regulator for diverse inflammatory cellular responses. Also, TRPA1 showed a unique, high sensitivity to oxidants including O2. Understanding the physiological significance of redox-sensitive TRPs will lead us to consider these TRP channels as viable therapeutic targets.

Research Products

• [Int'l Joint Research] トロント大学/ウェスタン大学(カナダ)
• [Int'l Joint Research] NIH(米国)
• [Journal Article] TRPC3 amplifies B cell receptor-induced ERK signaling via protein kinase D-dependent Rap1 activation (2016)
  • Author(s): T. Numaga-Tomita, M. Nishida, J.W. Jr. Putney and Y. Mori
  • Journal Title: Biochem J Volume: 473(2) Issue: 2 Pages: 201-210
  • DOI: 10.1042/bj20150596
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds (2016)
  • Author(s): S. Sawamura, M. Hatano, Y. Takada, K. Hino, T. Kawamura, J. Tanikawa, H. Nakagawa, H. Hase, A. Nakao, M. Hirano, R. Rotrattanadumrong, S. Kiyonaka, M.X. Mori, M. Nishida, Y. Hu, R. Inoue, R. Nagata and Y. Mori
  • Journal Title: Mol Pharmacol Volume: 89(3) Issue: 3 Pages: 348-363
  • DOI: 10.1124/mol.115.102863
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Different Contribution of Redox-Sensitive Transient Receptor Potential Channels to Acetaminophen-Induced Death of Human Hepatoma Cell Line (2016)
  • Author(s): Badr H, Kozai D, Sakaguchi R, Numata T, Mori Y
  • Journal Title: Front. Pharmacol. Volume: 7 Pages: 19-19
  • DOI: 10.3389/fphar.2016.00019
  • NAID: 120005848247
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TRPM2 channels in alveolar epithelial cells mediate bleomycin-induced lung inflammation (2016)
  • Author(s): Yonezawa R, Yamamoto S, Takenaka M, Kage Y, Negoro T, Toda T, Ohbayashi M, Numata T, Nakano Y, Yamamoto T, Mori Y, Ishii M, Shimizu S
  • Journal Title: Free Radic Biol Med Volume: 90 Pages: 101-113
  • DOI: 10.1016/j.freeradbiomed.2015.11.021
  • Peer Reviewed
• [Journal Article] The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment (2015)
  • Author(s): Ostapchenko VG, Chen M, Guzman MS, Xie YF, Lavine N, Fan J, Beraldo FH, Martyn AC, Belrose JC, Mori Y, MacDonald JF, Prado VF, Prado MA, Jackson MF
  • Journal Title: J. Neurosci. Volume: 35, Issue: 45 Pages: 15157-15169
  • DOI: 10.1523/jneurosci.4081-14.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transient receptor potential melastatin 2 protects mice against polymicrobial sepsis by enhancing bacterial clearance. (2014)
  • Author(s): Qian X, Numata T, Zhang K, Li C, Hou J, Mori Y & Fang X
  • Journal Title: Anesthesiology Volume: 121 Issue: 2 Pages: 336-351
  • DOI: 10.1097/aln.0000000000000275
  • Peer Reviewed
• [Journal Article] TRPM2 mediates the lysophosphatidic acid-induced neurite retraction in the developing brain. (2014)
  • Author(s): Jang Y, Lee MH, Lee J, Jung J, Lee SH, Yang DJ, Kim BW, Son H, Lee B, Chang S, Mori Y & Oh U
  • Journal Title: Pflugers Arch. Volume: 466 Issue: 10 Pages: 1987-1998
  • DOI: 10.1007/s00424-013-1436-4
  • Peer Reviewed / Open Access
• [Journal Article] TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2 (2014)
  • Author(s): Nobuaki Takahashi, Sayaka Hamada-Nakahara, Yuzuru Itoh, Kazuhiro Takemura, Atsushi Shimada,Yoshifumi Ueda, Manabu Kitamata, Rei Matsuoka, Kyoko Hanawa-Suetsugu, Yosuke Senju, Masayuki X. Mori, Shigeki Kiyonaka, Daisuke Kohda, Akio Kitao, Yasuo Mori and Shiro Suetsugu
  • Journal Title: Nature Communications Volume: 5 Issue: 1 Pages: 4994-4994
  • DOI: 10.1038/ncomms5994
  • NAID: 130005100825
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transnitrosylation directs TRPA1 selectivity in N-nitrosamine activators. (2014)
  • Author(s): Kozai D, Kabasawa Y, Ebert M, Kiyonaka S ; Finnan, Otani Y, Numata T, Takahashi N, Mori Y, Ohwada T.
  • Journal Title: Molecular Pharmacology Volume: 85 Issue: 1 Pages: 175-185
  • DOI: 10.1124/mol.113.088864
  • Peer Reviewed
• [Journal Article] Genetically encoded fluorescent thermosensors visualize subcellular thermoregulation in living cells (2013)
  • Author(s): Shigeki Kiyonaka, Taketoshi Kajimoto, Reiko Sakaguchi, Daisuke Shinmi, Mariko Omatsu-Kanbe, Hiroshi Matsuura, Hiromi Imamura, Takenao Yoshizaki, Itaru Hamachi, Takashi Morii, Yasuo Mori
  • Journal Title: Nature Methods Volume: 10 Issue: 12 Pages: 1232-1238
  • DOI: 10.1038/nmeth.2690
  • Peer Reviewed
• [Journal Article] TRP channels as sensors of oxygen availability. (2013)
  • Author(s): Numata T, Ogawa N, Takahashi N, Mori Y
  • Journal Title: Pflügers Archiv – European Journal of Physiology Volume: 465 Issue: 8 Pages: 1075-1085
  • DOI: 10.1007/s00424-013-1237-9
  • NAID: 120005474466
  • Peer Reviewed
• [Journal Article] Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischaemia/reperfusion injury (2013)
  • Author(s): Hiroi T, Wajima T, Negoro T, Ishii M, Yasuko Nakano, Kiuchi K, Mori Y, and Shimizu S
  • Journal Title: Cardiovasc Res Volume: vol.97 Issue: 2 Pages: 271-281
  • DOI: 10.1093/cvr/cvs332
  • Peer Reviewed
• [Journal Article] Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction. (2013)
  • Author(s): Liu X, Cotrim A, Teos L, Zheng C, Swaim W, Mitchell J, Mori Y, Ambudkar I
  • Journal Title: Nature Communication Volume: 4 Issue: 1 Pages: 1515-1515
  • DOI: 10.1038/ncomms2526
  • Peer Reviewed
• [Journal Article] TRPM2 links oxidative stress to NLRP3 inflammasome activation. (2013)
  • Author(s): Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, Qiao L
  • Journal Title: Nature Communication Volume: 4 Issue: 1 Pages: 1611-1611
  • DOI: 10.1038/ncomms2608
  • Peer Reviewed
• [Presentation] Genetically encoded fluorescent thermosensors visualize subcellular thermoregulation in living cells (2014)
  • Author(s): Kiyonaka S, Kajimoto T, ○Sakaguchi R, Shinmi D, Omatsu-Kanbe M, Matsuura H, Imamura H, Yoshizaki T, Hamachi I, Morii T, Mori Y
  • Organizer: 58th Annual Meeting of the Biophysical Society
  • Place of Presentation: California, USA
• [Presentation] 心臓TRPM2は、虚血・再灌流障害を増悪させる (2014)
  • Author(s): 沼田朋大、清水俊一、森泰生
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島県、鹿児島市
• [Remarks] 【森研究室】京都大学大学院工学研究科 合成・生物化学専攻 分子生物化学分野 森研究室
  • URL: http://www.sbchem.kyoto-u.ac.jp/mori-lab/