Joint international research for developing new drugs in the cerebral vascular diseases by targeting RAGE signaling

• Project/Area Number: 18KK0255
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kanazawa University
• Principal Investigator: 堀 修 金沢大学, 医学系, 教授 (60303947)
• Co-Investigator(Kenkyū-buntansha): 宝田 美佳 金沢大学, 医学系, 助教 (40565412) ; 石井 宏史 金沢大学, 医学系, 助教 (90634171)
• Project Period (FY): 2018-10-09 – 2024-03-31
• Project Status: Granted (Fiscal Year 2019)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2021: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2020: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 脳血管障害 / RAGEシグナル / 炎症

Outline of Annual Research Achievements

本研究で用いているRAGE/DIAPH1阻害化合物は、米国ニューヨーク大学のSchmidt教授がRAGEの細胞内シグナル伝達因子として細胞骨格関連分子DIAPH1を同定し(Hudson et al., J Biol Chem. 2008)、更にRAGEとDIAPH1の結合を阻害する化合物を探索することにより発見したものである(Manigrasso et al., Sci Rep.2016）。平成３０年度、この化合物の一つが、マウスくも膜下出血モデルにおいて脳血管攣縮予防効果及び症状改善効果を認めることを確認したが、令和元年度は、Schmidt教授との共同研究をさらに推進するため、若手研究者１名をSchmidtラボに派遣し、関連化合物についての最新の知見を得るとともに、現地でマウスくも膜下出血モデルを作製するための準備を行った。また、日本にSchmidt教授を招いて国際シンポジウム International symposium on diabetes and glycation biologyを開催し、RAGEシグナルの種々病態への関与について意見交換を行った。
更に、令和元年度は、RAGE/DIAPH1阻害化合物のマウス脳梗塞モデルにおいける効果についても検証した。具体的には、野生型マウスを用いて中大脳動永久脈閉塞モデルを作製し、数日を経た段階でRAGE/DIAPH1阻害化合物または溶媒を投与した。その後1週間した段階で行動試験を行い、神経症状を評価した。マウスは還流固定し、脳切片作製、HE染色にて脳梗塞巣の大きさを評価した。残念ながら今回の実験では、当該マウスに神経症状の改善、脳梗塞巣の大きさの縮小は認めなかった。今後、より早期の化合物投与について検討する必要があると考えられた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

若手研究者１名をSchmidtラボに派遣するとともに、日本にSchmidt教授を招聘して国際シンポジウムを開催し、国際共同研究を推進することが出きた。

Strategy for Future Research Activity

今後、若手研究員を再びSchmidtラボに派遣し、国際共同研究を加速させる。具体的には、RAGE化合物の投与法、投与時間の改良を行い、最適の方法を見出す。

Research Products

• [Int'l Joint Research] ニューヨーク大学(米国)
• [Int'l Joint Research] ニューヨーク大学(米国)
• [Journal Article] Does the superior fronto-occipital fascicle exist in the human brain? Fiber dissection and brain functional mapping in 90 patients with gliomas (2020)
  • Author(s): Liu Xiaoliang、Kinoshita Masashi、Shinohara Harumichi、Hori Osamu、Ozaki Noriyuki、Nakada Mitsutoshi
  • Journal Title: NeuroImage: Clinical Volume: 25 Pages: 102192-102192
  • DOI: 10.1016/j.nicl.2020.102192
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD38, CD157, and RAGE as Molecular Determinants for Social Behavior. (2019)
  • Author(s): .Higashida H, Hashii M, Tanaka Y, Matsukawa S, Higuchi Y, Gabata R, Tsubomoto M, Seishima N, Teramachi M, Kamijima T, Hattori T, Hori O, Tsuji C, Cherepanov SM, Shabalova AA, Gerasimenko M, Minami K, Yokoyama S, Munesue SI, Harashima A, Yamamoto Y, Salmina AB, Lopatina O.
  • Journal Title: Cells. Volume: 9(1) Issue: 1 Pages: 62-62
  • DOI: 10.3390/cells9010062
  • NAID: 120006859506
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroprotective Effects of Endogenous Secretory Receptor for Advanced Glycation End-products in Brain Ischemia (2019)
  • Author(s): Yu Shimizu, Ai Harashima, Seiichi Munesue, Masahiro Oishi, Tsuyoshi Hattori, Osamu Hori, Yasuko Kitao, Hiroshi Yamamoto, Nontaphat Leerach, Mitsutoshi Nakada, Yasuhiko Yamamoto, Yasuhiko Hayashi
  • Journal Title: Aging and Disease Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Soluble receptor for advanced glycation end products as a biomarker of symptomatic vasospasm in subarachnoid hemorrhage. (2019)
  • Author(s): Aida Y, Kamide T, Ishii H, Kitao Y, Uchiyama N, Nakada M, Hori O.
  • Journal Title: J Neurosurg. Volume: Nov 1 Issue: 1 Pages: 1-9
  • DOI: 10.3171/2019.8.jns191269
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deletion of CD38 Suppresses Glial Activation and Neuroinflammation in a Mouse Model of Demyelination (2019)
  • Author(s): Roboon Jureepon、Hattori Tsuyoshi、Ishii Hiroshi、Takarada-Iemata Mika、Le Thuong Manh、Shiraishi Yoshitake、Ozaki Noriyuki、Yamamoto Yasuhiko、Sugawara Akira、Okamoto Hiroshi、Higashida Haruhiro、Kitao Yasuko、Hori Osamu
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 13 Pages: 258-258
  • DOI: 10.3389/fncel.2019.00258
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Caspase-1 initiates apoptosis in the absence of gasdermin D (2019)
  • Author(s): Tsuchiya K, Nakajima S, SHosojima S, Nguyen DT, Hattori T, Le TM, Hori O, Mahib MR, Yamaguchi Y, Miura M, Kinoshita T, Kushiyama H, Sakurai M, Shiroishi T, Suda T
  • Journal Title: Nature Communications Volume: In press Issue: 1 Pages: 2091-2091
  • DOI: 10.1038/s41467-019-09753-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Caspase-1 initiates apoptosis in the absence of gasdermin D (2019)
  • Author(s): Tsuchiya K Nakajima S, Hosojima S, Nguyen DT, Hattori T, Le TM, Hori O, Mahib MR, Yamaguchi Y, Miura M, Kinoshita T, Kushiyama H, Sakurai M, Shiroishi T, Suda T
  • Journal Title: Nat Commun Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pre-administration of low-dose methamphetamine enhances movement and neural activity after high-dose methamphetamine administration in the striatum (2019)
  • Author(s): Takeichi T, Hori O, Hattori T, Kiryu K, Zuka M, Kitamura O
  • Journal Title: Neurosci Lett Volume: 703 Pages: 119-124
  • DOI: 10.1016/j.neulet.2019.03.023
  • Peer Reviewed / Open Access
• [Journal Article] Microglial activation in the cochlear nucleus after early hearing loss in rats. (2019)
  • Author(s): Noda M, Hatano M, Hattori T, Takarada-Iemata M, Shinozaki T, Sugimoto H, Ito M, Yoshizaki T, Hori O.
  • Journal Title: Auris Nasus Larynx. Volume: 印刷中 Issue: 5 Pages: 716-723
  • DOI: 10.1016/j.anl.2019.02.006
  • Peer Reviewed / Open Access
• [Journal Article] Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. (2019)
  • Author(s): Yamamoto Y, Liang M, Munesue S, Deguchi K, Harashima A, Furuhara K, Yuhi T, Zhong J, Akther S, Goto H, Eguchi Y, Kitao Y, Hori O, Shiraishi Y, Ozaki N, Shimizu Y, Kamide T, Yoshikawa A, Hayashi Y, Nakada M, Lopatina O, Gerasimenko M, Komleva Y, Malinovskaya N, Salmina AB, Asano M, Nishimori K, Higashida H et al.,
  • Journal Title: Commun Biol Volume: ２ Issue: 1 Pages: 76-76
  • DOI: 10.1038/s42003-019-0325-6
  • NAID: 120006605138
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of nuclear factor-κB p65 phosphorylation by 3,4-dihydroxybenzalacetone and caffeic acid phenethyl ester. (2018)
  • Author(s): Takakura K, Takatou S, Tomiyama R, Le TM, Nguyen DT, Nakamura Y, Konishi T, Matsugo S, Hori O.
  • Journal Title: J Pharmacol Sci Volume: 137(3) Issue: 3 Pages: 248-255
  • DOI: 10.1016/j.jphs.2018.07.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N-myc downstream-regulated gene 2 protects blood-brain barrier integrity following cerebral ischemia (2018)
  • Author(s): Takarada-Iemata Mika、Yoshikawa Akifumi、Ta Hieu Minh、Okitani Nahoko、Nishiuchi Takumi、Aida Yasuhiro、Kamide Tomoya、Hattori Tsuyoshi、Ishii Hiroshi、Tamatani Takashi、Le Thuong Manh、Roboon Jureepon、Kitao Yasuko、Matsuyama Tomohiro、Nakada Mitsutoshi、Hori Osamu
  • Journal Title: Glia Volume: 印刷中 Issue: 7 Pages: 1432-1446
  • DOI: 10.1002/glia.23315
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ndrg2 deficiency ameliorates neurodegeneration in experimental autoimmune encephalomyelitis (2018)
  • Author(s): Le Thuong Manh、Takarada-Iemata Mika、Ta Hieu Minh、Roboon Jureepon、Ishii Hiroshi、Tamatani Takashi、Kitao Yasuko、Hattori Tsuyoshi、Hori Osamu
  • Journal Title: Journal of neurochemistry Volume: 印刷中 Issue: 2 Pages: 139-153
  • DOI: 10.1111/jnc.14294
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Neuroprotective role of glial ATF6α pathway in optic nerve injury (2019)
  • Author(s): 宝田美佳、堀修
  • Organizer: 第42回日本神経科学大会・第62回日本神経化学会合同年会
• [Presentation] 脳発達と社会性行動におけるアストロサイトCD38の役割 (2019)
  • Author(s): 服部剛志、堀修
  • Organizer: 第49回日本神経精神薬理学会
  • Invited
• [Presentation] DAMPs-dependent neutrophil migration is critical pathology in cerebral vasospasm after SAH (2019)
  • Author(s): 石井宏史、堀修
  • Organizer: 第62回日本脳循環代謝学会
  • Invited
• [Presentation] 脳梗塞後のグリアストレス応答を介した神経血管保護作用 (2019)
  • Author(s): 宝田美佳、堀修
  • Organizer: 第42回日本分子生物学会
  • Invited
• [Presentation] 脳虚血病態におけるストレス応答性分子の保護的効果 (2018)
  • Author(s): 宝田美佳、堀修
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] Protective role of NDRG2 in blood-brain barrier integrity following ischemia (2018)
  • Author(s): 宝田美佳、堀修
  • Organizer: International Conference on Neurovascular and Neurodegenerative Diseases
  • Invited
• [Presentation] アストロサイトCD38による神経発達制御機構 (2018)
  • Author(s): 服部剛志、堀修
  • Organizer: 日本解剖学会 第78回中部支部学術集会
• [Presentation] Peripheral leukocyte accumulation in the brain is critical pathology of cerebral vasospasm/neuronal dysfunction after subdural arachnoid hemorrhage (2018)
  • Author(s): 石井宏史、堀修
  • Organizer: 日本解剖学会 第78回中部支部学術集会
• [Presentation] 視神経傷害後の網膜神経節細胞生存における小胞体ストレス応答ATF6経路の役割 (2018)
  • Author(s): 宝田美佳、堀修
  • Organizer: 日本解剖学会 第78回中部支部学術集会
• [Presentation] The role of CD38 for neuronal and glial development (2018)
  • Author(s): 服部剛志、堀修
  • Organizer: 第61回日本神経化学会
• [Presentation] アストロサイトによる脳梗塞後の血液脳関門制御 (2018)
  • Author(s): 宝田美佳、堀修
  • Organizer: 第61回日本神経化学会
• [Remarks] 金沢大学医薬保健研究域医学系 神経解剖学
  • URL: http://med03.w3.kanazawa-u.ac.jp/
• [Funded Workshop] International Symposium on Chronic Disease and Glycation Biology (2020)
• [Funded Workshop] New Frontier in Neuroscience 2020― International Symposium on Neural Development, Regeneration & Diseases (2020)
• [Funded Workshop] International Symposium on Chronic Disease and Glycation Biology (2019)