The role of a secreted protein Reelin in the brain and its therapeutic application.
| Project/Area Number |
17H03985
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Nagoya City University |
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Principal Investigator |
Hattori Mitsuharu 名古屋市立大学, 医薬学総合研究院(薬学), 教授 (60272481)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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| Keywords | 脳 / 精神疾患 / 神経発達 / リーリン / プロテアーゼ / 神経細胞移動 / メタロプロテアーゼ / アルツハイマー病 / ノックアウトマウス / リン酸化 / 遺伝子改変マウス |
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| Outline of Final Research Achievements |
Reelin is important in the neuronal development and counteracting amyloid β toxicity. A specific proteolytic cleavage of Reelin abolishes its biological activity. We identified ADAMTS-3 as the major enzyme that inactivates Reelin in the brain. We also found that ADAMTS-2 is expressed in the adult brain at approximately the same level as ADAMTS-3. We generated ADAMTS-2 knockout (KO) mice and found that ADAMTS-2 significantly contributes to the N-t inactivation of Reelin in the postnatal cerebral cortex and hippocampus, but much less in the cerebellum. Therefore, it was suggested that ADAMTS-2 can be a therapeutic target for adult brain disorders such as schizophrenia and Alzheimer's disease.
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| Academic Significance and Societal Importance of the Research Achievements |
WHOによると、精神神経疾患による損失年数（DALY）は非感染性疾患の1/4を占め、新規治療へのニーズが極めて高い疾患領域である。特に我が国を含む先進国においては、高齢化や高度なストレスを要因としてその患者数は増加しており、経済損失や治療コストも増加の一途を辿っている。しかし、精神神経疾患に関しては現状、病態の理解も不充分であり、その創薬の成功確度は他の疾患分野に比べて低く、停滞している。本研究の主要な部分は基礎研究であるが、既に製薬企業との共同研究を開始しており、応用研究も一部開始した。リーリンの研究では世界的でも最先端に位置し、新理論の確立も視野に入れる申請となっている。
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Report
(4 results)
Research Products
(69 results)
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[Journal Article] Detachment of Chain-Forming Neuroblasts by Fyn-Mediated Control of cell-cell Adhesion in the Postnatal Brain.2018
Author(s)
Fujikake K, Sawada M, Hikita T, Seto Y, Kaneko N, Herranz-Perez V, Dohi N, Homma N, Osaga S, Yanagawa Y, Akaike T, Garcia-Verdugo JM, Hattori M, Sobue K, Sawamoto K.
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Journal Title
Journal of Neuroscience
Volume: 38
Issue: 19
Pages: 4598-4609
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia.2018
Author(s)
Sobue A, Kushima I, Nagai T, Shan W, Kohno T, Aleksic B, Aoyama Y, Mori D, Arioka Y, Kawano N, Yamamoto M, Hattori M, Nabeshima T, Yamada K, Ozaki N.
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Journal Title
Sci Rep.
Volume: 8
Issue: 1
Pages: 13046-13046
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Reelin deficiency leads to aberrant lipid composition in mouse brain.2018
Author(s)
Mizukami T, Ikeda K, Shimanaka Y, Korogi K, Zhou C, Takase H, Tsuiji H, Kono N, Kohno T, Arai H, Arita M, Hattori M.
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Journal Title
Biochem Biophys Res Commun
Volume: 505
Issue: 1
Pages: 81-86
DOI
Related Report
Peer Reviewed
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[Journal Article] Secreted Metalloproteinase ADAMTS-3 Inactivates Reelin2017
Author(s)
Ogino H, Hisanaga A, Kohno T, Kondo Y, Okumura K, Kamei T, Sato T, Asahara H, Tsuiji H, Fukata M, Hattori M
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Journal Title
J Neurosci
Volume: 37
Issue: 12
Pages: 3181-3191
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Secreted Metalloproteinase ADAMTS-3 Inactivates Reelin2017
Author(s)
Himari Ogino, Arisa Hisanaga, Takao Kohno, Eisuke Okugawa, Tomoha Ohsima, Yuta Kondo, Kyoko Okumura, Takana Kamei, Tempei Sato, Hiroshi Asahara, Hitomi Tsuiji, Masaki Fukata, Mitsuharu Hattori
Organizer
第40回 日本神経科学大会
Related Report
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[Presentation] To clarify how Reelin affects the lipid compositions of neurons2017
Author(s)
Katsunari Korogi, Tomoharu Mizukami, Chunyu Zhou, Takao Kohno, Fumiyoshi Yamazaki, Katsuya Kabashima, Yuta Shimanaka, Kazutaka Ikeda, Hiroyuki Arai, Makoto Arita, Mitsutoshi Setou, Mitsuharu Hattori
Organizer
ConBio2017
Related Report
