| Budget Amount *help |
¥72,410,000 (Direct Cost: ¥55,700,000、Indirect Cost: ¥16,710,000)
Fiscal Year 2023: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
Fiscal Year 2022: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
Fiscal Year 2021: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
Fiscal Year 2020: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2019: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
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| Outline of Final Research Achievements |
Amyotrophic Lateral Sclerosis (ALS) is the most intractable neurological disease, and we have revealed that Zn, metallothionein, Zn transporter and related miRNAs are involved in intracellular aggregation, cytotoxicity, oxidation and various stresses such as endoplasmic reticulum as a pathological mechanism of ALS. Among idiopathic basal ganglia calcification (IBGC) cases, we found that 40-50% of familial cases had SLC20A2 mutation and 10% had PDGFB mutation in Japanese cases. We generated iPS cells from the patients and differentiated them into vascular endothelial cells to reproduce each phenotype. Molecular mechanisms of neuronal damage caused by low heavy metal (Hg) load and low zinc load during embryonic period were elucidated. The studies revealed that biometals play an important role in the pathogenesis of each neurodegenerative disease, opening the way for new drug discovery.
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| Academic Significance and Societal Importance of the Research Achievements |
ALSの療薬薬候補とし、HSP-70, HGF, IGF-1などの各種神経栄養因子とZnを豊富に含んだヒト乳歯歯髄幹細胞培養上清 (SHED-CM)で孤発性および家族性ALS患者由来iPS細胞から誘導した運動ニューロンでその有用性を実証した。IBGCの発症基盤はPi代謝異常で高Pi状態が、主に毛細血管周囲腔において重金属と錯体を形成し、石灰顆粒を形成し、重合してゆくことがこの疾患の本体であることを明らかにし、根本的治療への道を開いた。他にもパーキンソン病、ダウン症候群などの神経変性疾患の発症機序で、当初の予想を超えて特定の生命金属が重要な役割を果たしていることを明らかにした。
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