Development of novel drugs for improving cognitive impairment

• Project/Area Number: 20500340
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Keio University
• Principal Investigator: MISAWA Hidemi Keio University, 薬学部, 教授 (80219617)
• Co-Investigator(Kenkyū-buntansha): OKUDA Takashi 慶應義塾大学, 薬学部, 講師 (00322040)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 神経創薬 / 認知症 / トランスポーター / ニコチン受容体 / アセチルコリン

Research Abstract

In order to develop a novel drug intervention for improving disease-related or age-related cognitive impairment, we focused our research on two potential drug targets; high-affinity choline transporter 1 (CHT1) & alpha7-type nicotinic acetylcholine receptor (α7 nAChR). We established an assay system to monitor CHT1 trafficking in cultured cells and screened >1,000 chemicals, and eventually obtained a few seed chemicals that affected CHT1 trafficking. And besides we demonstrated, for the first time, neuronal localization of SLURP1, a putative endogenous allosteric ligand for α7 nAChR.

Research Products

• [Journal Article] Sustained subcutaneous infusion of nicotine enhances cholinergic vasodilation in the cerebral cortex induced by stimulation of the nucleus basalis of Meynert in rats. (2011)
  • Author(s): Uchida, S., Hotta, H., Misawa, H., 他
  • Journal Title: Eur.J.Pharmacol. 654 Pages: 238-240
  • Peer Reviewed
• [Journal Article] Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. (2010)
  • Author(s): Hideyama, T., Yamashita, T., Suzuki, T., Tsuji, S., Higuchi, M., Seeburg, P.H., Takahashi, R., Misawa, H., Kwak, S.
  • Journal Title: J.Neurosci. 30 Pages: 11917-11925
  • Peer Reviewed
• [Journal Article] miRNA malfunction causes spinal motor neuron disease. (2010)
  • Author(s): Haramanti, S., Chapnik, E., Sztainbreg, H., Eilam-Altstadter, R., Zwang, R., Gershoni, N., McGlinn, E., Heiser, P.W., Wills, A-M., Wirguin, I., Rubin, L., Misawa, H., Tabin C.J., Brown Jr.R., Chen, A., Hornstein, E.
  • Journal Title: Proc.Natl.Acad.Sci.USA 107 Pages: 13111-13116
  • Peer Reviewed
• [Journal Article] Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. (2010)
  • Author(s): Hideyama T., et al.
  • Journal Title: J.Neurosci. Volume: 30 Pages: 11917-11925
  • Peer Reviewed
• [Journal Article] Down-regulation of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1(SLURP-1), an endogenous allosteric α7 nicotinic acetylcholine receptor modulator, in murine and human asthmatic conditions. (2010)
  • Author(s): Narumoto O., et al.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 398 Pages: 713-718
  • Peer Reviewed
• [Journal Article] miRNA malfunction causes spinal motor neuron disease. (2010)
  • Author(s): Haramanti S., et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA. Volume: 107 Pages: 13111-13116
  • Peer Reviewed
• [Journal Article] Primary sensory neuronal expression of SLURP-1, an endogenous nicotinic acetylcholine receptor ligand. (2009)
  • Author(s): Moriwaki, Y., Watanabe, Y., Shinagawa, T., Kai, M., Miyazawa, M., Okuda, T., Kawashima, K., Yanbashi, A., Waguri, S., Misawa, H.
  • Journal Title: Neurosci.Res. 64 Pages: 403-412
  • Peer Reviewed
• [Journal Article] Expression of SLURP-1, an endogenous alpha7 nicotinic acetylcholine receptor allostreric ligand, in murine bronchial epithelial cells. (2009)
  • Author(s): Horiguchi, K., Horiguchi, S., Yamashita, N., Irie, K., Masuda, J., Takano-Ohmuro, H., Himi, T., Miyazawa, M., Moriwaki, Y., Okuda, T., Misawa, H., Ozaki, H., Kawashima, K.
  • Journal Title: J.Neurosci.Res. 87 Pages: 2740-2747
  • Peer Reviewed
• [Journal Article] Primary sensory neuronal expression of SLURP-1, an endogenous nicotinic acetylcholine receptor ligand. (2009)
  • Author(s): Moriwaki Y., et al.
  • Journal Title: Neurosci.Res. 64 Pages: 403-412
  • Peer Reviewed
• [Journal Article] Acetylcholine synthesis and release in NIH3T3 cells coexpressing the high-affinity choline transporter and choline acetyltransferase. (2009)
  • Author(s): Fujii T., et al.
  • Journal Title: J.Neurosci.Res. 87 Pages: 3024-3032
  • Peer Reviewed
• [Journal Article] Expression of SLURP-1, an endogenous alpha7 nicotinic acetylcholine receptor allosteric ligand, in murine bronchial epithelial cells. (2009)
  • Author(s): Horiguchi K., et al.
  • Journal Title: J.Neurosci.Res. 87 Pages: 2740-2747
  • Peer Reviewed
• [Journal Article] Role of GluR1 in activity-dependent motor system development. (2008)
  • Author(s): Zhang, L., Schessl, J., Werner, M., Bonnemann, C., Xiong, G., Mojsilovic-Petrovic, J., Zhou, W., Cohen, A., Seeburg, P., Misawa, H., Jayaram, A., Personius, K., Hollmann, M., Sprengel, R., Kalb, R.
  • Journal Title: J.Neurosci. 28 Pages: 9953-9968
  • Peer Reviewed
• [Journal Article] Aberrant trafficking of the high-affinity choline transporter in AP-3-deficient mice (2008)
  • Author(s): Misawa, H., Fujigaya, H., Nishimura, T., Moriwaki, Y., Okuda, T., Kawashima, K., Nakata, K., Ruggiero, A.M., Blakely, R.D., Nakatsu, F., Ohno, H.
  • Journal Title: Eur.J.Neurosci. 27 Pages: 3109-3117
  • Peer Reviewed
• [Journal Article] Astrocytes as determinants of disease progression in inherited ALS. (2008)
  • Author(s): Yamanaka, K., Chun, S.J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D.H., Takahashi, R., Misawa, H., Cleveland, D.W.
  • Journal Title: Nature Neurosci. 11 Pages: 251-253
  • Peer Reviewed
• [Journal Article] Role of GluRl in activity-dependent motor system development. (2008)
  • Author(s): Zhang L., et al.
  • Journal Title: J. Neurosci. 25 Pages: 9953-9968
  • Peer Reviewed
• [Journal Article] Aberrant trafficking of the high-affinity choline transporter in AP-3-deficient mice. (2008)
  • Author(s): Misawa H., et al.
  • Journal Title: Eur. J. Neurosci. 27 Pages: 3109-3117
  • Peer Reviewed
• [Presentation] シナプス小胞トランスボーターの細胞内移行モチーフの探索 (2010)
  • Author(s): 神保美紗子, 他2名
  • Organizer: 第84回日本薬理学年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2010-03-23
• [Presentation] テトラヒドロピリミジン系薬の新たな中枢作用点の同定 (2010)
  • Author(s): 小西麻未, 他
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪市
  • Year and Date: 2010-03-18
• [Presentation] テトラヒドロピリミジン系薬の新たな中枢神経作用点の同定 (2010)
  • Author(s): 小西麻未, 他3名
  • Organizer: 第83回日本薬理学年会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2010-03-18
• [Presentation] テトラヒドロピリミジン系薬の新たな中枢作用点の同定 (2009)
  • Author(s): 野村有希, 他
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2009
  • Place of Presentation: 東京
  • Year and Date: 2009-08-24
• [Presentation] 高親和性コリントランスポーターの細胞内移行 (2009)
  • Author(s): 奥田隆志, 他
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: 横浜市
  • Year and Date: 2009-03-18
• [Presentation] ニコチン性アセチルコリン受容体内在性アロステリックリガンドSLURP1の一次知覚神経での発現 (2008)
  • Author(s): 三澤日出巳, 他
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 東京
  • Year and Date: 2008-07-10
• [Presentation] ニコチン性アセチルコリン受容体の内在性アロステリツクリガンドSLURP-1の一次知覚神経での発現 (2008)
  • Author(s): 三澤日出巳, 他4名
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 横浜市
  • Year and Date: 2008-07-10
• [Book] ブレインサイエンスレビュー2010(認知症のトライアングル仮説とコリン作動性ニューロン0 (2010)
  • Author(s): 三澤日出巳
  • Publisher: クバプロ