Purification of HCNP receptor for new drug development

• Project/Area Number: 20K07891
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Nagoya City University
• Principal Investigator: Matsukawa Noriyuki 名古屋市立大学, 医薬学総合研究院(医学), 教授 (20305543)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アルツハイマー病 / HCNP / 受容体 / Ach / ＨＣＮＰ / コリン作動性神経

Outline of Research at the Start

アルツハイマー病では、進行した病理変化があっても認知症を発症しない症例が存在するが、そのメカニズムは不明である（Cognitive reserve: CR）。申請者の研究室では、記憶メカニズムの観点から、海馬神経活動を調節するコリン作動性神経に着目し、中隔核アセチルコリン産生を促進する海馬由来コリン作動性神経ペプチド(HCNP)を発見した。HCNP過剰発現海馬では、アミロイドオリゴマーによる神経活動抑制が軽減できることを明らかにした。これらの成果を踏まえ、今回の申請では、新たな創薬に向けた標的開発を目指してHCNP受容体単離を目的とする。

Outline of Final Research Achievements

We previously reported hippocampal cholinergic neurostimulating peptide (HCNP) as a candidate of regulator gene for septo-hippocampal cholinergic network, and its knockout mice displayed cholinergic dysfunction in septo-hippocampal formation and the administration of HCNP into ventricle could rescue function. In this proposal, the aim of study is to purify the receptor of HCNP. We established the Ach-producing cell by HCNP stimulation from human umbilical cells, and mesurement system of Ach at fmol level by LC-mass spectrometer. We identified two candidate of HCNP receptor, P2RY6 and BMPR2, by genechip analysis. In the future, we will verify if each candidate might be receptor of HCNP by using genetically modified cells.

Academic Significance and Societal Importance of the Research Achievements

抗アミロイド治療が現実味を帯びてきたが、機能改善における効果は限定的な可能性がある。パーキンソン病治療を鑑みても疾患修飾に加えて、機能改善薬開発を継続する意義は期待される。歴史的に使用されるコリンエステラーゼ阻害薬は、Ach分泌細胞死により機能がなくなる。Ach分泌を維持したり、更に細胞保護効果を有する薬剤開発は機能改善効果を持続する可能性が期待される。本研究は、機能改善期間を少しでも長くすることを期待した創薬に向けた研究である。

Research Products

• [Journal Article] Reduction of acetylcholine ion the hippocampus of hippocampus cholinergic neurostimulating peptide precursor protein knockout mice (2021)
  • Author(s): Kondo-Takuma Y, Mizuno M, Tsuda Y, madokoro Y, Suzuki K, Sato T, takase H, Uchida Y, Adachi KI, Hida H, Borlongan CV, Matsukawa N.
  • Journal Title: Sci Rep Volume: 11(1) Issue: 1
  • DOI: 10.1038/s41598-021-01667-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The unsolved mystery of hippocampal cholinergic neurostimulating peptide: A potent cholinergic regulator (2021)
  • Author(s): Justin Y Cho, Noriyuki Matsukawa
  • Journal Title: Brain Circ. Volume: 7 Issue: 1 Pages: 29-32
  • DOI: 10.4103/bc.bc_14_21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impairment of the visuospatial working memory in the patients with Parkinson's Disease: an fMRI study. (2021)
  • Author(s): Kawashima S, Shimizu Y, Ueki Y, Matsukawa N.
  • Journal Title: BMC Neurol. Volume: 21(1) Issue: 1 Pages: 335-335
  • DOI: 10.1186/s12883-021-02366-7
  • Peer Reviewed / Open Access
• [Journal Article] Rapid Progression of White Matter Signal Changes and Frontotemporal Atrophy in Globular Glial Tauopathy (2021)
  • Author(s): Ohno Y, Matsukawa N et al.
  • Journal Title: J Neuropathol Exp Neurol . Volume: 80(5) Issue: 5 Pages: 480-483
  • DOI: 10.1093/jnen/nlaa151
  • Peer Reviewed
• [Journal Article] The Feasibility of Mechanical Thrombectomy on Single-Plane Angiosuite: An In-Depth Analysis of Procedure Time (2021)
  • Author(s): Inoue H, Oomura M, Nishikawa Y, Mase M, Matsukawa N.
  • Journal Title: Cerebrovasc Dis Extra. Volume: 11 Issue: 3 Pages: 112-117
  • DOI: 10.1159/000519555
  • Peer Reviewed / Open Access
• [Journal Article] Possible correlated variation of GABA A receptor α3 expression with hippocampal cholinergic neurostimulating peptide precursor protein in the hippocampus (2021)
  • Author(s): Adachi K, Matsukawa N et al.
  • Journal Title: Biochem Biophys Res Commun . Volume: 542 Pages: 80-86
  • DOI: 10.1016/j.bbrc.2021.01.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Iron leakage owing to blood?brain barrier disruption in small vessel disease CADASIL (2020)
  • Author(s): Uchida Yuto、Kan Hirohito、Sakurai Keita、Arai Nobuyuki、Inui Shohei、Kobayashi Susumu、Kato Daisuke、Ueki Yoshino、Matsukawa Noriyuki
  • Journal Title: Neurology Volume: 95 Issue: 9
  • DOI: 10.1212/wnl.0000000000010148
  • Peer Reviewed
• [Journal Article] Magnetic Susceptibility Associates with Dopaminergic Deficits and Cognition in Parkinson's Disease. (2020)
  • Author(s): Uchida Y, Kan H, Sakurai K, Inui S, Kobayashi S, Akagawa Y, Shibuya K, Ueki Y, Matsukawa N.
  • Journal Title: Mov Disord Volume: in press Issue: 8 Pages: 1396-1405
  • DOI: 10.1002/mds.28077
  • Peer Reviewed