The role and mechanisms of TORC and HDAC signaling pathway and therapeutic new-class small compounds for neurological disease

• Project/Area Number: 24390222
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: sasaki tsutomu 大阪大学, 医学部附属病院, 助教 (20534879)
• Co-Investigator(Kenkyū-buntansha): kitagawa kazuo 東京女子医科大学, 医学部, 教授 (70301257) ; nagaoka yasuo 関西大学, 工学部, 教授 (90243039) ; takemori hiroshi 国立研究開発法人医薬基盤, 健康・栄養研究所, プロジェクトリーダー (90273672)
• Co-Investigator(Renkei-kenkyūsha): mochiduki hideki 大阪大学, 医学系研究科, 教授 (90230044) ; uesato shinnichi 関西大学, 工学部, 教授 (50111969)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2012: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: 脳虚血 / シグナルトランスダクション / ＣＲＥＢ / ＳＩＫ（塩誘導性キナーゼ） / ＨＤＡＣ（ヒストン脱アセチル化酵素） / パーキンソン病 / ＨＤＡＣ阻害剤 / 創薬 / CRTC / SIK（塩誘導性キナーゼ） / HDAC / アポトーシス / CREB / エピゲノム / TORC / 低分子化合物 / 神経疾患 / 脳卒中

Outline of Final Research Achievements

Although patients suffering from neurological disease including both neurodegenerative disease and stroke will increase dramatically in the coming years, there are currently a few effective drugs for neuronal protection and disease-modifying therapy. To provide new therapies to overcome these disease, we have examined both roles and mechanisms of salt-inducible kinase (SIK)-CREB-CRTC signaling and both histone deacetylases (HDACs) - histone acetylation. These cascade has been attributed to both not only neuronal injury but also inflammation in many neurological diseases. Among the original HDAC inhibitor library, we identified a novel HDAC1/2 isoform-specific inhibitor for Parkinson's disease and stroke. The isoform selective inhibition of HDAC may pave the way to new strategies for neurological disease.

Research Products

• [Journal Article] A novel histone deacetylase 1 and 2 isoform-specific inhibitor alleviates experimental Parkinson's disease. (2016)
  • Author(s): Choong CJ, Sasaki T, Hayakawa H, Yasuda T, Baba K, Hirata Y, Uesato S, Mochizuki H.
  • Journal Title: Neurobiology of Aging Volume: 37 Pages: 103-116
  • DOI: 10.1016/j.neurobiolaging.2015.10.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Discovery of new low-molecular-weight p53-Mdmx disruptors and their anti-cancer activities (2016)
  • Author(s): Uesato, S.; Matsuura, Y.; Matsue, S.; Sumiyoshi, T.; Hirata, Y.; Takemoto, S.; Kawaratani, Y.; Yamai, Y.; Ishida, K.; Sasaki, T.; Enari, M.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 8 Pages: 1919-1926
  • DOI: 10.1016/j.bmc.2016.03.021
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Serine racemase inhibition induces nitric oxide-mediated neurovascular protection during cerebral ischemia (2016)
  • Author(s): Watanabe A, Sasaki T, Kanki H, Yukami T, Takemori H, Sakaguchi M, Kitagawa K, Mochizuki H
  • Journal Title: Neuroscience Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors. (2016)
  • Author(s): Hatate J, Miwa K, Matsumoto M, Sasaki T, Yagita Y, Sakaguchi M, Kitagawa K, Mochizuki H.
  • Journal Title: Parkinsonism Relat Disord. Volume: Feb 13. pii: S1353-8020(16) Pages: 30039-6
  • DOI: 10.1016/j.parkreldis.2016.02.011
  • Peer Reviewed
• [Journal Article] Characteristics of cryptogenic stroke in cancer patients (2016)
  • Author(s): Gon Y, Okazaki S, Terasaki Y, Sasaki T, Yoshimine T, Sakaguchi M, Mochizuki H.
  • Journal Title: Ann Clin Transl Neurol. Volume: Feb 11;3(4) Issue: 4 Pages: 280-7
  • DOI: 10.1002/acn3.291
  • Peer Reviewed / Open Access
• [Journal Article] Chronic Elevation of Tumor Necrosis Factor-α Mediates the Impairment of Leptomeningeal Arteriogenesis in db/db Mice. (2015)
  • Author(s): Yukami T, Yagita Y, Sugiyama Y, Oyama N, Watanabe A, Sasaki T, Sakaguchi M, Mochizuki H, Kitagawa K.
  • Journal Title: Stroke Volume: 46 Issue: 6 Pages: 1657-63
  • DOI: 10.1161/strokeaha.114.008062
  • Peer Reviewed / Open Access
• [Journal Article] Granulocyte colony-stimulating factor fails to enhance leptomeningeal collateral growth in spontaneously hypertensive rats (2014)
  • Author(s): Sugiyama Y, Yagita Y, Yukami T, Watanabe A, Oyama N, Terasaki Y, Omura-Matsuoka E, Sasaki T, Mochizuki H, Kitagawa K
  • Journal Title: Neurosci Lett Volume: 564 Pages: 16-20
  • DOI: 10.1016/j.neulet.2014.01.053
  • Peer Reviewed / Open Access
• [Journal Article] Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line. (2014)
  • Author(s): Ayako Kumagai, Akira Fujita, Tomoki Yokoyama, Yuki Nonobe, Yasuhiro Hasaba, Tsutomu Sasaki, Yumi Itoh, Minako Koura, Osamu Suzuki, Shigeki Adachi, Haruko Ryo, Arihiro Kohara, Lokesh P. Tripathi, Masato Sanosaka, Toshiki Fukushima, Taisei Nomura, Hiroshi Takemori, et al.
  • Journal Title: Genes Volume: 5 Issue: 4 Pages: 1095-1114
  • DOI: 10.3390/genes5041095
  • Peer Reviewed / Open Access
• [Journal Article] Sasaki T, Choong CJ, Watanabe A, Hirata Y, Sanosaka M, Yukami T, Kitagawa K, Takemori H, Uesato S, Mochizuki H. (2014)
  • Author(s): Efficacy and implications of selective class I or II Histone deacetylase inhibitors for ischemic brain injury.
  • Journal Title: Ann of Neurology Special Issue Volume: Vol 76(suppl 18) Issue: S18
  • DOI: 10.1002/ana.24247
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Functional deterioration of endothelial nitric oxide synthase after focal cerebral ischemia (2013)
  • Author(s): Yagita Y, Kitagawa K, Oyama N, Yukami T, Watanabe A, Sasaki T, Mochizuki H
  • Journal Title: J Cereb Blood Flow Metab Volume: 33 Issue: 10 Pages: 1532-9
  • DOI: 10.1038/jcbfm.2013.112
  • Peer Reviewed
• [Journal Article] Involvement of SIK3 in Glucose and Lipid Homeostasis in Mice (2012)
  • Author(s): Uebi T, Itoh Y, Hatano O, Kumagai A, Sanosaka M, Sasaki T, Sasagawa S, Doi J, Tatsumi K, Mitamura K, Morii E, Aozasa K, Kawamura T, Okumura M, Nakae J, et al.
  • Journal Title: PLoS One Volume: 7 Issue: 5 Pages: e37803-e37803
  • DOI: 10.1371/journal.pone.0037803
  • Peer Reviewed
• [Journal Article] CREB activation is a key player for ischemic tolerance in the brain . (2012)
  • Author(s): Kitagawa K, Sasaki T, et. al.
  • Journal Title: Rinsho Shinkeigaku. Volume: 52(11) Pages: 904-2
  • NAID: 130004505204
  • Peer Reviewed
• [Journal Article] Suppression of dynamin GTPase decreases alpha-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy. (2012)
  • Author(s): Konno M, Hasegawa T, Baba T, Miura E, Sugeno N, Kikuchi A, Fiesel FC, Sasaki T, Aoki M, Itoyama Y, Takeda A.
  • Journal Title: Mol Neurodegener Volume: 7 Issue: 1 Pages: 38-38
  • DOI: 10.1186/1750-1326-7-38
  • Peer Reviewed
• [Presentation] Efficacy and implications of isoform selective Histone deacetylase inhibitors for cerebral ischemia (2016)
  • Author(s): Sasaki T, Chonng Chi-Jing, Watanabe A, Kanki H, Yukami T, Hayakawa H, Yasuda T, Baba K, Sakaguchi M, Uesato S, Mochizuki H
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Presentation] Serine racemase inhibition induces NO-mediated neurovascular protection during cerebral ischemia (2016)
  • Author(s): Watanabe A, Sasaki T, Kanki H, Yukami T, Takemori H, Sakaguchi M, Mochizuki H
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Presentation] Effect of thrombin and cAMP-PKA signaling on the angiogenesis in brain microvasculature (2016)
  • Author(s): Kanki H, Sasaki T, Watanabe A, Yukami T, Sakaguchi M, Mochizuki H
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Presentation] Selective inhibition of NR2B attenuates ischemic neuronal injury in neuronal culture and rats (2016)
  • Author(s): Terasaki Y, Sasaki T, Yukami T, Oyama N, Yagita Y, Sakaguchi M, Kitagawa K, Mochizuki H
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Presentation] Novel HDAC1/2 isoform-specific inhibitor K560 ameliorates MPP+/MPTP-mediated experimental Parkinson’s disease (2016)
  • Author(s): Chi-Jing Choong, Tsutomu Sasaki, Hideki Hayakawa, Toru Yasuda, Kousuke Baba, Yoshiyuki Hirata, Shinichi Uesato, and Hideki Mochizuki
  • Organizer: AOPMC 2016 (5th Asian and Oceanian Parkinson’s Disease and Movement Disorders Congress)
  • Place of Presentation: MANILA, PHILIPPINES
  • Year and Date: 2016-03-11
  • Int'l Joint Research / Invited
• [Presentation] A novel histone deacetylase 1 and 2 isoform-specific inhibitor alleviates experimental Parkinson's disease. (2015)
  • Author(s): Chi-Jing Choong, Tsutomu Sasaki, Hideki Hayakawa, Toru Yasuda, Kousuke Baba, Yoshiyuki Hirata, Shinichi Uesato, and Hideki Mochizuki
  • Organizer: XXI World Congress on Parkinson’s Disease and Related Disorders. IAPRD 2015
  • Place of Presentation: Milan, Italy
  • Year and Date: 2015-12-06
  • Int'l Joint Research / Invited
• [Presentation] アイソフォーム特異的HDAC阻害剤による虚血性脳血管障害の治療検討 (2015)
  • Author(s): 佐々木 勉、鐘 其静、渡邊 彰弘、神吉 秀明、馬場 孝輔、 平田 佳之、坂口 学、上里 新一、望月 秀樹
  • Organizer: 第33回日本神経治療学会総会 The 33rd Annual Meeting of Japanese Society of Neurological Therapeutics
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-26
• [Presentation] 脳虚血におけるPGC-1αシグナルの調節機構の検討 (2015)
  • Author(s): 佐々木 勉、渡邊 彰弘、神吉 秀明、由上 登志郎、竹森 洋、坂口 学、望月 秀樹
  • Organizer: 第27回日本脳循環代謝学会総会
  • Place of Presentation: 富山
  • Year and Date: 2015-10-30
• [Presentation] 脳虚血におけるSRR-Serineの役割について (2015)
  • Author(s): 渡邊 彰弘、佐々木 勉、神吉 秀明、由上 登志郎、竹森 洋、坂口 学、望月 秀樹
  • Organizer: 第27回日本脳循環代謝学会総会
  • Place of Presentation: 富山
  • Year and Date: 2015-10-30
• [Presentation] Efficacy and implications of selective class I or II Histone deacetylase inhibitors for neurological disorders. (2015)
  • Author(s): CJ Choong, T Sasaki, H Hayakawa, K Baba, Watanabe A, Y Hirata, S Uesato and H Mochizuki
  • Organizer: 17th Annual Meeting of the American Society for Experimental NeuroTherapeutics (ASENT 2015)
  • Place of Presentation: Georgetown University Hotel And Conference Center, District of Columbia, Washington, USA
  • Year and Date: 2015-02-19
  • Int'l Joint Research
• [Presentation] Efficacy and implications of selective class I or II Histone deacetylase inhibitors for ischemic brain injury. (2014)
  • Author(s): Sasaki T, Choong CJ, Watanabe A, Hirata Y, Sanosaka M, Yukami T, Kitagawa K, Takemori H, Uesato S, Mochizuki H.
  • Organizer: American Neurological Association's 2014 Annual Meeting
  • Place of Presentation: Baltimore Marriott Waterfront Hotel, Maryland, USA
  • Year and Date: 2014-10-12
  • Int'l Joint Research
• [Presentation] 脳虚血時のCRTC-PGC-1αシグナルの動態 (2014)
  • Author(s): 佐々木 勉、 北川一夫、 八木田佳樹、 由上登志郎、佐野坂真人、 八木田佳樹、 竹森 洋、 望月秀樹
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡県福岡市博多区
  • Year and Date: 2014-05-21
• [Presentation] 2型糖尿病では脳軟膜動脈吻合の発達は障害される (2014)
  • Author(s): 由上登志郎、 八木田佳樹、渡邊彰弘、佐々木勉、坂口学、望月秀樹、北川一夫
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡県福岡市博多区
  • Year and Date: 2014-05-21
• [Presentation] 脳虚血におけるCRTC-PGC-1αシグナルの動態についての検討 (2014)
  • Author(s): 佐々木 勉、 渡邊彰弘、 神吉秀明、 由上登志郎、 竹森 洋、 坂口 学、 望月秀樹
  • Organizer: 第51回日本臨床分子医学会総会
  • Place of Presentation: 東京国際フォーラム、東京都千代田区
  • Year and Date: 2014-04-11
• [Presentation] 脳虚血におけるCRTC-PGC-1αシグナルの動態についての検討 (2014)
  • Author(s): 佐々木勉、竹森 洋、渡邊 彰弘、由上登志郎、北川一夫、望月秀樹
  • Organizer: 臨床分子医学会総会
  • Place of Presentation: 東京
• [Presentation] ニコチン性アセチルコリン受容体活性化による神経保護作用の検討 (2014)
  • Author(s): 佐々木勉、北川一夫、渡邉彰弘、竹森 洋、渡邊 彰弘、由上登志郎、竹森 洋、望月秀樹
  • Organizer: 日本脳卒中学会(Stroke2014)
  • Place of Presentation: 大阪
• [Presentation] ニコチンによる神経保護機構の検討 (2013)
  • Author(s): 佐々木勉、北川一夫、渡邊彰弘、 由上登志郎、八木田佳樹、竹森 洋 、望月秀樹
  • Organizer: 第54回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] A Role of CREB-CRTC signaling in nicotine-induced neuroprotection. (2013)
  • Author(s): T Sasaki, K Kitagawa, A Watanabe, T Yukami, N Oyama, Y Yagita, H Takemori, and H Mochizuki
  • Organizer: Brain 2013
  • Place of Presentation: Shanghai, China
• [Presentation] ニコチンによるCREB活性化を介した神経保護機構の検討 (2012)
  • Author(s): 佐々木勉
  • Organizer: 第24回日本脳循環代謝学会総会
  • Place of Presentation: 広島
  • Year and Date: 2012-11-09
• [Presentation] 中枢神経系におけるCRTC-CREB制御機構とその役割 (2012)
  • Author(s): 佐々木勉
  • Organizer: 第24回日本脳循環代謝学会総会
  • Place of Presentation: 広島(招待講演)
  • Year and Date: 2012-11-08
• [Presentation] A Role of CREB-CRTC signaling in nicotine-mediated neuroprotection (2012)
  • Author(s): Sasaki Tsutomu
  • Organizer: Neuroscience2012(第35回日本神経科学会総会)
  • Place of Presentation: Nagoya
  • Year and Date: 2012-09-18
• [Presentation] 脳虚血耐性時における塩誘導性キナーゼ(SIK)-CRTC経路の動態。 (2012)
  • Author(s): 佐々木勉
  • Organizer: 第53回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-25
• [Patent(Industrial Property Rights)] 含窒素複素環誘導体、神経保護剤及びがん治療用医薬組成物 (2015)
  • Inventor(s): 佐々木勉、望月秀樹、Choong CJ、上里新一、住吉孝之
  • Industrial Property Rights Holder: 佐々木勉、望月秀樹、Choong CJ、上里新一、住吉孝之
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-09-09
  • Overseas
• [Patent(Industrial Property Rights)] アシルアミノフェニル基を有する化合物及びその用途 (2015)
  • Inventor(s): 佐々木勉、望月秀樹、Choong CJ、上里新一、住吉孝之
  • Industrial Property Rights Holder: 佐々木勉、望月秀樹、Choong CJ、上里新一、住吉孝之
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-11-25
  • Overseas
• [Patent(Industrial Property Rights)] アイソフォーム特異的新規 HDAC 阻害剤による神経疾患治療法の開発 (2014)
  • Inventor(s): 佐々木勉、望月秀樹、Choong CJ、上里新一、平田佳之
  • Industrial Property Rights Holder: 佐々木勉、望月秀樹、Choong CJ、上里新一、平田佳之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-183239
  • Filing Date: 2014-09-09
• [Patent(Industrial Property Rights)] 新規含窒素複素環誘導体 (2014)
  • Inventor(s): 上里新一、住吉孝明、平田佳之、望月秀樹、佐々木 勉
  • Industrial Property Rights Holder: 上里新一、住吉孝明、平田佳之、望月秀樹、佐々木 勉
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-183235
  • Filing Date: 2014-09-09
• [Patent(Industrial Property Rights)] アシルアミノフェニル基を有する化合物及びその用途 (2014)
  • Inventor(s): 佐々木勉、望月秀樹、Choong CJ、上里新一
  • Industrial Property Rights Holder: 佐々木勉、望月秀樹、Choong CJ、上里新一
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-237826
  • Filing Date: 2014-11-25