| Project/Area Number |
16K08274
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pharmacology in pharmacy
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| Research Institution | Tokyo University of Science (2018)
Nagasaki University (2016-2017) |
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Principal Investigator |
ASAI Masashi 東京理科大学, 薬学部生命創薬科学科, 助教 (90383223)
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| Co-Investigator(Kenkyū-buntansha) |
岩田 修永 長崎大学, 医歯薬学総合研究科(薬学系), 教授 (70246213)
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| Research Collaborator |
MORI Ryotaro
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | アルツハイマー病 / ダウン症 / 21番染色体 / アミロイドβペプチド / DYRK1A / ネプリライシン / リン酸化 |
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| Outline of Final Research Achievements |
To develop a cure for Alzheimer’s disease, I focused people with Down syndrome that have an early onset of Alzheimer’s disease. An extra copy of chromosome 21 causes Down syndrome. Therefore, I investigated the relationship between dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) encoded in chromosome 21 Down syndrome critical region and neprilysin identified as a major Aβ-degrading enzyme. I found that the activity of nerprilysin in fibroblasts derived from people with Down syndrome was significantly lower than that in healthy controls. The protein expression levels of neprilysin were also decreased. The long-term pharmacological inhibition of calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, in which are excessively suppressed in people in Down syndrome, caused a significant decrease in the activity of neprilysin. Taken together, these results suggest that DYRK1A is a potential drug target for Alzheimer’s disease treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
2020年には65歳以上の認知症の有病者は600万人に達すると予想され、その半数以上はアルツハイマー病と見積もられている。依然としてアルツハイマー病はアンメットメディカルニーズの高い代表疾患であり、現在臨床使用されている薬剤は症状改善薬で、病態修飾薬は存在しない。また、ダウン症者の平均寿命は60歳になろうとしており、早期からアルツハイマー病を発症するため、アルツハイマー病の根本的治療薬の開発は喫緊の課題となっている。本研究成果によって示唆された21番染色体に存在するキナーゼとアミロイド分解酵素の相互作用は、アルツハイマー病に対する副作用の少ない新しい薬剤開発の標的となり得る。
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