Molecular dissection of tryptophan metabolism in emotional behavior and its related is diseases.

• Project/Area Number: 23590362
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Asahikawa Medical College
• Principal Investigator: FUNAKOSHI Hiroshi 旭川医科大学, 医学部, 教授 (40273685)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: tryptophan / tryptophan dioxygenase / indoleamine dioxygenase / キヌレニン / 情動 / 代謝 / ノックアウトマウス / TDO / トリプトファン（Trp） / Tryptophan dioxygenase / Indoleamine dioxygenase / キヌレニン（KYN） / ノックアウトマウス（KOマウス） / Tryptophan / トリプトファン / セロトニン / トリプトファン2,3-ジオキシゲナーゼ / トリプトファン 2,3-ジオキシゲナーゼ / 精神神経疾患

Research Abstract

Tryptophan (Trp) is metabolized via there major pathways; the serotonergic , transaminergic and kynurenergic (Kyn) pathways, and the Kyn pathway contributes about 95% of Trp metabolism. Therefore it has been thought that the elucidation of the roles of Kyn pathway may unvail the roles of Trp metabolisms in a variety of functions, including emotional behaviors. However, because of the presence of two restriction enzymes in Kyn pathway, it has been limited for the analyses of these enzymes in vivo. Here we have generated TDO-KO mice and elucidated the roles of TDO in (1) tryptophan metabolism in the systemic circulation and brain (2) tryptophan metabolismsincluding NAD in different food conditions (3) higher brain function as well as immunological function and (4) emotional disease.

Research Products

• [Journal Article] The kynurenine pathway contributes to long-term neuropsychological changes in experimental pneumococcal meningitis. (2014)
  • Author(s): Too LK, McQuillan J, Ball H, Kanai M, Nakamura T, Funakoshi H, McGregor I, Hunt N
  • Journal Title: Behavioural Brain Research Volume: in press Pages: 179-195
  • DOI: 10.1016/j.bbr.2014.05.018
  • Peer Reviewed
• [Journal Article] (2014)
  • Author(s): Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, Bicciato S, Mazza EM, Macchiarulo A, Vacca C, Iannitti R, Tissi L, Volpi C, Belladonna ML,Orabona C, Bianchi R, Lanz TV, Platten M, Della Fazia MA, Piobbico D, Zelante T, Funakoshi H, et al
  • Journal Title: Nature Volume: 511 Issue: 7508 Pages: 184-190
  • DOI: 10.1038/nature13323
• [Journal Article] Contributions of Tryptophan 2,3-dioxygenase and Indoleamine 2,3-dioxygenase to the Conversion of D-Tryptophan to Nicotinamide Analyzed by using Tryptophan 2,3-dioxygenase -Knockout Mice (2014)
  • Author(s): Maeta A, Sano M, Fukuwatari T, Funakoshi H, Nakamura T, Shibata K
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 78 Issue: 5 Pages: 1-4
  • DOI: 10.1080/09168451.2014.905185
• [Journal Article] Contributions of Tryptophan 2,3-dioxygenase and Indoleamine 2,3-dioxygenase to the Conversion of D-Tryptophan to Nicotinamide Analyzed by using Tryptophan 2,3-dioxygenase -Knockout Mice (2014)
  • Author(s): Maeta A, Sano M, Fukuwatari T, Funakoshi H, Nakamura T, and Shibata K
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: in press
  • Peer Reviewed
• [Journal Article] Aryl hydrocarbon receptor control of a disease tolerance defense pathway (2014)
  • Author(s): Puccetti P, Gargaro M, Pallotta M, Matino D, Vacca C, Volpi C, Belladonna M, Orabona C, Bianchi R, Grohmann U, Fallarino F, Iannitti R, Tissi L, Zelante T, Romani L, Servillo G, Brunacci C, Fazia MD, Piobbico D, Bessede A, Bicciato S, Mazza E, Macchiarulo A, Lanz T, Platten M, Funakoshi H et al.
  • Journal Title: Nature Volume: in press
  • Peer Reviewed
• [Journal Article] The niacin required for optimum growth can be synthesized from L-tryptophan in growing mice lacking tryptophan-2,3-dioxygenase. (2013)
  • Author(s): Terakata M, Fukuwatari T, Kadota E, Sano M, Kanai M, Nakamura T, Funakoshi H, Shibata K
  • Journal Title: J Nutr Volume: 143(7) Issue: 7 Pages: 1046-51
  • DOI: 10.3945/jn.113.176875
  • Peer Reviewed
• [Journal Article] Tryptophan-restriction diets help to maintain L-tryptophan homeostasis in tryptophan 2,3-dioxygenase knockout mice (2013)
  • Author(s): Maeta A, Fukuwatari T, Funakoshi H, Nakamura T, Shibata K
  • Journal Title: Int J Tryptophan Res. Volume: 6(Suppl 1) Pages: 55-65
  • DOI: 10.4137/ijtr.s12206
  • NAID: 120005293327
• [Journal Article] te amount of niacin required for optimum growth in growing mice can be synthesized from L-tryptophan without tryptophan 2,3-dioxygenase. (2013)
  • Author(s): Miki Terakata, Tsutomu Fukuwatari, Eri Kadota, Mitsue Sano, Masaaki Kanai, Toshikazu Nakamura, Hiroshi Funakoshi, Katsumi Shibata
  • Journal Title: Journal of Nutrition Volume: in press
  • Peer Reviewed
• [Journal Article] Tryptophan-restriction diets help to maintain L-tryptophan homeostasis in tryptophan 2,3-dioxygenase knockout mice (2013)
  • Author(s): Akihiro Maeta, Tsutomu Fukuwatari, Hiroshi Funakoshi, Toshikazu Nakamura, and Katsumi Shibata
  • Journal Title: International Journal of Tryptophan Research Volume: in press
  • NAID: 120005293327
  • Peer Reviewed
• [Journal Article] Overexpression of HGF attenuates the degeneration of Purkinje cells and Bergmann glia in a knockin mouse model of spinocerebellar ataxia type 7 (2012)
  • Author(s): Noma S, Ohya-Shimada W, Kanai M, Ueda K, Nakamura T, Funakoshi H
  • Journal Title: Neurosci Res.(Corresponding author) Volume: 773(2) Pages: 115-121
• [Journal Article] Hepatocyte growth factor (HGF) overexpression in the nervous system enhances learning and memory performance in mice (2012)
  • Author(s): Kato T, Funakoshi H, Kadoyama K, Noma S, Kanai M, Ohya-Shimada W, Mizuno S, Doe N, Taniguchi T, Nakamura T
  • Journal Title: J. Neurosci. Res. (Corresponding authors) Volume: 90(9) Pages: 1743-1755
• [Journal Article] Hepatocyte growth factor overexpression in the nervous system enhances learning and memory performance in mice (2012)
  • Author(s): Kato T, Funakoshi H, Kadoyama K, Noma S, Kanai M, Ohya-Shimada W, Mizuno S, Doe N, Taniguchi T, Nakamura T
  • Journal Title: J. Neurosci. Res Volume: 90(9) Issue: 9 Pages: 1743-55
  • DOI: 10.1002/jnr.23065
  • Peer Reviewed
• [Journal Article] Overexpression of HGF attenuates the degeneration of Purkinje cell sand Bergmann glia in a knockin mouse model of spinocerebellar ataxia type 7 (2012)
  • Author(s): Noma S, Ohya-Shimada W, Kanai M, Ueda K, Nakamura T, Funakoshi H.
  • Journal Title: Neurosci. Res Volume: 73 Issue: 2 Pages: 115-121
  • DOI: 10.1016/j.neures.2012.03.001
  • Peer Reviewed
• [Journal Article] Therapeutic role of regenerative factor "HGF" in ALS and other neurodegenerative disorders (2012)
  • Author(s): Funakoshi H, Nakamura T
  • Journal Title: Rinsho Shinkeigaku Volume: 52(11) Pages: 942-942
  • NAID: 130004505219
  • Peer Reviewed
• [Journal Article] Overexpression of HGF attenuates the degeneration of Purkinje cells and Bergmann glia in a knockin mouse model of spinocerebellar ataxia type 7 (2012)
  • Author(s): Noma S, Ohya-Shimada W, Kanai M, Nakamura T, and Funakoshi H.
  • Journal Title: Neurosci Res. Volume: 73(2) Pages: 115-21
  • Peer Reviewed
• [Journal Article] Human Hepatocyte Growth Factor Promotes Functional Recovery in Primates after Spinal Cord Injury (2011)
  • Author(s): Kitamura K, Fujiyoshi K, Yamane J, Toyota F, Hikishima K, Nomura T, Funakoshi H, Nakamura T, Aoki M, Toyama Y, Okano H, Nakamura M.
  • Journal Title: PLOS one Volume: 6 Issue: 11 Pages: e27706-e27706
  • DOI: 10.1371/journal.pone.0027706
  • Peer Reviewed
• [Journal Article] Strong neurogenesis, angiogenesis and anti-fibrosis of hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion (tMCAO) (2011)
  • Author(s): Shang J, Deguchi K, Ohta Y, Liu N, Zhang X, Tian F, Yamashita T, Ikeda Y, Matsuura T, Funakoshi H, Nakamura T, Abe K
  • Journal Title: J Neurosci Res Volume: 89(1) Pages: 86-95
• [Journal Article] Modulation of Tryptophan Metabolism, promotion of neurogenesis and Alteration of Anxiety-Related Behavior in Tryptophan 2,3-Dioxygenase-Deficient Mice (2011)
  • Author(s): Funakoshi H., Kanai M., and Nakamura T.
  • Journal Title: International Journal of Tryptophan Research Volume: 4 Pages: 7-18
  • Peer Reviewed
• [Journal Article] Hepatocyte Growth Factor (HGF): Neurotrophic Functions and Therapeutic Implications for Neuronal Injury/Diseases (2011)
  • Author(s): Funakoshi H., and Nakamura T
  • Journal Title: Current Signal Transduction Therapy Volume: 6 Pages: 156-167
  • Peer Reviewed
• [Journal Article] Therapeutic Potential of Hepatocyte Growth Factor for Treating Neurological Diseases (2011)
  • Author(s): Kadoyama K., Kadoyama K., Funakoshi H., Nakamura T., Sakaeda T.
  • Journal Title: Current Drug Therapy Volume: 19, 6(3) Pages: 7-206
  • Peer Reviewed
• [Journal Article] Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury. (2011)
  • Author(s): Kitamura K, Fujiyoshi K, Yamane J, Toyota F, Hikishima K, Nomura T, Funakoshi H, Nakamura T, Aoki M, Toyama Y, Okano H, Nakamura M.
  • Journal Title: PLoS One Volume: 6(11)
  • Peer Reviewed
• [Journal Article] Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion. (2011)
  • Author(s): Shang J, Deguchi K, Ohta Y, Liu N, Zhang X, Tian F, Yamashita T, Ikeda Y, Matsuura T, Funakoshi H, Nakamura T, Abe K.
  • Journal Title: J Neurosci Res. Volume: 89(1) Pages: 86-95
  • Peer Reviewed
• [Presentation] Tissue relationship (e.g. brain vs periphery) in Trp metabolism (2012)
  • Author(s): Funaksohi H., Kanai. M., Nakamura T.
  • Organizer: 13th ISTRY Satellite Symposium
  • Place of Presentation: Brisbane, Australia.
  • Invited
• [Presentation] Indoleamine 2,3-dioxygenase predominantly regulates circulating kynurenine levels dependent on plasma tryptophan levels, which are controlled by tryptophan 2,3-dioxygenase, in vivo (2012)
  • Author(s): Kanai M., Ohyama F., Tone S., Nakamura T., Funakoshi H.
  • Organizer: The 13th International Society for Tryptophan Research (ISTRY) meeting, Syndey, Australia.
  • Place of Presentation: Syndey, Australia.
• [Presentation] Roles of tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase in higher brain functions (2012)
  • Author(s): Funakoshi H, Kanai M., Nakamura T.
  • Organizer: The 13th International Society for Tryptophan Research (ISTRY) meeting,.
  • Place of Presentation: Syndey, Australia.
• [Presentation] HGFは生理的学習機能を亢進する (2012)
  • Author(s): 船越 洋、加藤 貴史、野間 さつき、金井 将昭1、島田（大谷）若菜、 水野 信哉、 土江 信隆、谷口 泰三、角山 圭一、中村 敏一
  • Organizer: 厚生労働省班会議
  • Place of Presentation: 東京
• [Presentation] 再生因子による神経疾患治療法開発を目指して (2012)
  • Author(s): 船越 洋
  • Organizer: 第74回旭川医科大学フォーラム
  • Place of Presentation: 旭川
• [Presentation] 「こころ」の発達におけるトリプトファン代謝酵 素Tryptophan 2,3-dioxygenase の生理的役割 (2011)
  • Author(s): 金井 将昭、船越 洋、中村 敏一
  • Organizer: 第84 回 日本生化学会
  • Place of Presentation: 京都
• [Presentation] マウス妊娠初期におけ るトリプトファン分解酵素IDO およびTDO の発現. (2011)
  • Author(s): 大山文男、金井将昭、中村敏一、船越洋、栗林太、刀祢重信.
  • Organizer: 第84 回 日本生化学会
  • Place of Presentation: 京都
• [Presentation] 中枢神経におけるHGF 遺伝 子の過剰発現はマウスの記憶・学習機能を向上させる (2011)
  • Author(s): 加藤 貴史、船越 洋、角山 圭一、野間 さつき、金井 将昭、島田（大谷）若菜、水 野 信哉、土江 伸誉、谷口 泰造、松山 正剛、中村敏一.
  • Organizer: 中枢神経におけるHGF 遺伝 子の過剰発現はマウスの記憶・学習機能を向上させる
  • Place of Presentation: 京都
• [Presentation] 「こころ」の発達におけるトリプトファン代謝酵 素Tryptophan 2,3-dioxygenase の生理的役割 (2011)
  • Author(s): 金井 将昭、中村 敏一、船越 洋
  • Organizer: 第13 回ペット栄養学会
  • Place of Presentation: 東京
• [Presentation] Differential effects on systemic kynurenine levels by TDO and IDO under physiological conditions and interferon treatment. (2011)
  • Author(s): T. V. Lanz, P. P. Ho, M. Kanai, H. Funakoshi, T. Nakamura, L. Steinman, W. Wick, and M. Platten
  • Organizer: 5th Joint Tri.congress Eur. Ame.Com. Treat.Res.MS.
  • Place of Presentation: オランダ
• [Presentation] TDO と IDO は異なる機序で血中キヌレニン量を 調節する. (2011)
  • Author(s): 金井 将昭、中村 敏一、船越 洋
  • Organizer: 第5 回アミノ酸学会
  • Place of Presentation: 名古屋
• [Presentation] TDO と IDO は異なる機 序で循環血液中のキヌレニンレベルを調節する. (2011)
  • Author(s): 金井 将昭、中村 敏一、大山 文男、刀祢 重信、船越 洋
  • Organizer: 第33 回トリプトファン研究会
  • Place of Presentation: 千葉
• [Presentation] マウス妊娠初期におけ るトリプトファン分解酵素IDO およびTDO の発現. (2011)
  • Author(s): 大山文男、金井将昭、中村敏一、船越洋、栗林太、刀祢重信
  • Organizer: 第33 回トリプトファン研究会
  • Place of Presentation: 千葉
• [Presentation] ヒトトリプトファン2,3-ジオキシゲナーゼの3次元立体構造の同定と精神疾患への意義 (2011)
  • Author(s): 船越 洋、金井 将昭、中村 敏一
  • Organizer: 第422回研究協議会（ビタミンB研究委員会）
  • Place of Presentation: 大津
• [Presentation] 再生因子（HGF）の神経系における機能と神経再生医療への展開の可能性（トピックス）
  • Author(s): 船越 洋、中村 敏一
  • Organizer: 第19回日本血液代替物学会年次大会
  • Place of Presentation: 旭川
  • Invited
• [Presentation] トリプトファン代謝と脳機能
  • Author(s): 船越 洋、金井 将昭、中村 敏一
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: 茨木
  • Invited
• [Remarks]
  • URL: http://www.asahikawa-med.ac.jp/arec/funakoshis_labo/
• [Remarks]
  • URL: http://www.asahikawa-med.ac.jp/arec/
• [Remarks] 旭川医科大学教育研究推進センター 船越研究室
  • URL: http://www.asahikawa-med.ac.jp/arec/funakoshis_labo/
• [Remarks] 旭川医科大学教育研究推進センター
  • URL: http://www.asahikawa-med.ac.jp/arec/
• [Remarks] 旭川医科大学教育研究推進センター 船越研究室
  • URL: http://www.asahikawa-med.ac.jp/arec/funakoshis_labo/research.html
• [Remarks] 旭川医科大学教育研究推進センター
  • URL: http://www.asahikawa-med.ac.jp/arec/