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KAKEN_26117007seika.pdf
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Title |
Title |
ヒトiPS細胞と霊長類モデルを用いた治療開発の基盤整備
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ヒト iPS サイボウ ト レイチョウルイ モデル オ モチイタ チリョウ カイハツ ノ キバン セイビ
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Hito iPS saibō to reichōrui moderu o mochiita chiryō kaihatsu no kiban seibi
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Establishment of brain protein aging models; human iPS cell model and non-human primate model
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岡野, 栄之
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オカノ, ヒデユキ
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Okano, Hideyuki
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慶應義塾大学・医学部 (信濃町)・教授
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Research team head
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科研費研究者番号 : 60160694
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塩澤, 誠司
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シオザワ, セイジ
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Shiozawa, Seiji
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Research team member
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池内, 健
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イケウチ, タケシ
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Ikeuchi, Takeshi
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Collaborator
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2019
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科学研究費補助金研究成果報告書
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2018
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Abstract |
脳タンパク質老化に起因する神経変性疾患の治療法を開発する上で、神経細胞の変性及び神経細胞死に至る機構の解明が直近の課題である。本研究では、タウR406W変異患者よりiPS細胞の樹立し、神経細胞への分化誘導を行った。これらの細胞を用いて解析を行ったところ、タウR406W変異患者iPS細胞由来神経細胞タウのリン酸化や局在異常、軸索変性などの異常を認めた。また、治療法の臨床応用を目指す際には、よりヒトに近い霊長類における動物モデルが望まれる。そこで、変異タウを発現するトランスジェニックマーモセットの作出を試みたが、個体作出には至らず、内在性遺伝子のゲノム編集など異なるアプローチの必要性が示唆された。
For the potential development of novel therapeutic strategies for tauopathies, our group established a tauopathy model bearing tau mutations associated with frontotemporal dementia with parkinsonism-17 (FTDP-17) for investigating tau pathology and for usage in drug screening. For this purpose, we generated iPSCs from 2 frontotemporal dementia patients of a Japanese pedigree bearing the tau R406W mutation. To examine the phenotypes in neurons, we developed efficient cortical neural differentiation methods for iPSCs using small molecules. In this neuronal culture, the mutant tau exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. Collectively, our findings provide new mechanistic insight into tau pathology and a potential for therapeutic intervention.
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研究種目 : 新学術領域研究(研究領域提案型)
研究期間 : 2014~2018
課題番号 : 26117007
研究分野 : 神経科学
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