精密創薬研究部
研究部紹介
私たちは、次世代の創薬支援ツールを開発し、医薬品候補化合物の安全性・有効性・薬物動態評価を精密に行いながら、画期的な治療戦略を生み出す研究部です。実験薬理研究室と分子薬理研究室の二本柱で構成され、創薬と成育医療の革新を同時に推進し、独創的なアイデアと最先端技術を駆使して未来の医薬品開発をリードします。最先端の生命科学と臨床に基づく医学との融合を通して、これまでにないバイオ医学研究を推進しており、特に高度なイメージング技術によって、動的な病態の再現に基づく疾患研究という新たな学問分野を開拓しています。
次世代の医薬品、細胞製剤、そして創薬支援ツールの開発を通じて、患者さん一人一人に最適な治療を届けるよう、基礎研究を推進しています。
研究内容
- 神経オルガノイドを用いた発生学的基礎研究
ヒト多能性幹細胞から創った３次元脳組織(神経オルガノイド)の技術をもとに、大脳皮質、海馬、脊髄などの神経領域を３次元で作成します。ヒト神経組織の解析を通して、ヒトに特異的な発生バックグラウンドを明らかにします。 - 神経オルガノイドを用いた疾患モデリング研究
患者さん由来のiPS細胞を用いて神経オルガノイドを作成することで、疾患バックグラウンドを有した脳組織の作成が可能となります。疾患のメカニズム解明、及び創薬研究へと発展させてゆきます。 - 中枢・末梢神経系の髄鞘発生学と髄鞘変性を伴う神経疾患学
基礎研究としてのオリゴデンドロサイトやシュワン細胞による髄鞘形成のメカニズム解明研究を行っています。得られた知見をもとに、Pelizaeus-Merzbacher病やCharcot-Marie-Tooth病などの遺伝性脱髄疾患の治療標的因子の探索と病態メカニズムの解明へと発展させていきます。 - 神経オルガノイドの倫理研究
人文系学者と連携して科学・医学側の知見を多面的に解釈してゆくことで、新たにヒト脳組織を作る神経オルガノイド研究の利益と懸念を適切に評価しつつ、将来的に社会に十分還元可能な研究として発展できるよう、課題の整理・解決を行っています。
1.Hiroaki Oizumi*, Yuki Miyamoto*, Chika Seiwa, Masahiro Yamamoto, Nozomu Yoshioka, Seiichi Iizuka, Tomohiro Torii, Katsuya Ohbuchi, Kazushige Mizoguchi, Junji Yamauchi, and Hiroaki Asou.
Lethal adulthood myelin breakdown by oligodendrocyte-specific Ddx54 knockout.
iScience. 26, 107448 (2023) * equally contributed
2.Yuki Miyamoto, Tomohiro Torii, Keiichi Homma, Hiroaki Oizumi, Katsuya Ohbuchi, Kazushige Mizoguchi,
Shou Takashima, and Junji Yamauchi.
The adaptor SH2B1 and the phosphatase PTP4A1 regulate the phosphorylation of cytohesin-2 in myelinating Schwann cells in mice.
Sci. Signal. 15(3), eabi5276 (2022)
3.Yuki Miyamoto*, Tomohiro Torii, Miho Terao, Shuji Takada, Akito Tanoue, Hironori Katoh, and
Junji Yamauchi.
Rnd2 differentially regulates oligodendrocyte myelination at different developmental periods.
Mol. Biol. Cell 32, 769-787 (2021): *Corresponding author
4.Takahiro Kitahara, Hideya Sakaguchi*, Asuka Morizane, Tetsuhiro Kikuchi, Susumu Miyamoto, Jun
Takahashi*.
Axonal extensions along corticospinal tracts from transplanted human cerebral organoids.
Stem Cell Reports. Aug 11;15(2):467-481 (2020) *Corresponding author
5.Yuki Miyamoto, Marina Tanaka, Hisanaka Ito, Hiroaki Ooizumi, Katsuya Ohbuchi, Kazushige Mizoguchi, Tomohiro Torii, and Junji Yamauchi.
Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice.
Biochem. Biophys. Res. Commun. 531, 445-451 (2020)
6.Hideya Sakaguchi*, Yuki Ozaki, Tomoka Ashida, Takayoshi Matsubara, Naotaka Oishi, Shunsuke Kihara, Jun Takahashi*. Self-organized synchronous calcium transients in a cultured human neural network derived from cerebral organoids. Stem Cell Reports. 13(3):458-473 (2019) *Corresponding author
7.Tsutomu Sawai*, Hideya Sakaguchi*, Elizabeth Thomas, Jun Takahashi, Misao Fujita. The ethics of cerebral organiod research: Being conscious of consciousness. Stem Cell Reports.13(3):440-447 (2019) *Corresponding author
8.Takenori Ogura†, Hideya Sakaguchi†*, Susumu Miyamoto, Jun Takahashi J*.
Three-dimensional induction of dorsal, intermediate and ventral spinal cord tissues from human pluripotent stem cells. Development.145(16):dev162214. (2018) *Corresponding author †: co-first author
9.Yuki Miyamoto, Tomohiro Torii, Kenji Tago, Akito Tanoue, Shou Takashima, and Junji Yamauchi.
BIG1/Arfgef1 and Arf1 regulate the initiation of myelination by Schwann cells in mice.
Sci. Adv. 4, eaar4471 (2018)
10.Yuki Miyamoto, Tomohiro Torii, Akito Tanoue, and Junji Yamauchi.
VCAM1 acts in parallel with CD69 and is required for the initiation of oligodendrocyte myelination.
Nat. Commun. 7, 13478 (2016)
11.Hideya Sakaguchi*, Taisuke Kadoshima, Mika Soen, Nobuhiro Narii, Yoshihito Ishida, Masatoshi Ohgushi, Jun Takahashi, Mototsugu Eiraku*, Yoshiki Sasai. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun. Nov 17;6:8896 (2015) *Corresponding author
12.Yuki Miyamoto, Tomohiro Torii, Shuji Takada, Nobuhiko Ohno, Yurika Saitoh, Kazuaki Nakamura,
Akihito Ito, Toru Ogata, Nobuo Terada, Akito Tanoue, and Junji Yamauchi.
Involvement of the Tyro3 receptor and its intracellular partner Fyn signaling in Schwann cell myelination.
Mol. Biol. Cell 26, 3489-3503 (2015)
13.Yuki Miyamoto, Natsuki Yamamori, Tomohiro Torii, Akito Tanoue, and Junji Yamauchi. Rab35, acting through ACAP2 switching off Arf6, negatively regulates oligodendrocyte differentiation and myelination.
Mol. Biol. Cell 25, 1532-1542 (2014)
14.Taisuke Kadoshima, Hideya Sakaguchi, Tokushige Nakano, Mika Soen, Satoshi Ando, Mototsugu Eiraku,
Yoshiki Sasai. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A. 110(50):20284-20289 (2013)
15.Fabrizio Piazza, Steven M Greenberg, Mario Savoiardo, Margherita Gardinetti, Luisa Chiapparini, Irina Raicher, Ricardo Nitrini, Hideya Sakaguchi, Monica Brioschi, Giuseppe Billo, Antonio Colombo, Francesca Lanzani, Giuseppe Piscosquito, Maria Rita Carriero, Giorgio Giaccone, Fabrizio Tagliavini, Carlo Ferrarese, Jacopo C DiFrancesco. Anti-Aβ autoantibodies in Cerebral Amyloid Angiopathy-related inflammation: implications for amyloid-modifying therapies.
Ann. Neurol. 73(4):449-458 (2013)
16.Yuki Miyamoto, Tomohiro Torii, Natsuki Yamamori, Toru Ogata, Akito Tanoue, and Junji Yamauchi.
Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons.
Sci. Signal. 6, ra15 (2013)
17.Hideya Sakaguchi*, Satoshi Yamashita, Teruyuki Hirano, Makoto Nakajima, En Kimura, Yasushi Maeda, Makoto Uchino. Myasthenic crisis patients who require intensive care unit management. Muscle & Nerve 46:440-442 (2012) *Corresponding author
18.Junji Yamauchi, Yuki Miyamoto, Tomohiro Torii, Shou Takashima, Kazumi Kondo, Katsumasa Kawahara,
Noriko Nemoto, Jonah R. Chan, Gozoh Tsujimoto, and Akito Tanoue. Phosphorylation of cytohesin-1 by Fyn is required for initiation of myelination and the extent of myelination during development. Sci. Signal. 5, ra69 (2012)
19.Yuki Miyamoto, Tomohiro Torii, Akito Tanoue, and Junji Yamauchi.
Pelizaeus-Merzbacher disease-associated proteolipid protein 1 inhibits oligodendrocyte precursor cell differentiation via extracellular-signal regulated kinase signaling.
Biochem. Biophys. Res. Commun. 424, 262-268 (2012)
20.Hideya Sakaguchi*, Akihiko Ueda, Takayuki Kosaka, Satoshi Yamashita, En Kimura, Taro Yamashita, Yasushi Maeda, Teruyuki Hirano, Makoto Uchino. Cerebral amyloid angiopathy-related inflammation presenting with steroid-responsive higher brain dysfunction: case report and review of the literature. J. Neuroinflammation 8:116 (2011) *Corresponding author
21.Hideya Sakaguchi, Satoshi Yamashita, Akiko Miura, Tomoo Hirahara, En Kimura, Yasushi Maeda, Tadashi Terasaki, Teruyuki Hirano, Makoto Uchino. A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot-Marie-Tooth disease. J. Neurol. 258:284-90 (2011)
22.Junji Yamauchi, Yuki Miyamoto, Hajime Hamasaki, Atsushi Sanbe, Shinji Kusakawa, Akane Nakamura, Hideki Tsumura, Masahiro Maeda, Noriko Nemoto, Katsumasa Kawahara, Tomohiro Torii, and Akito Tanoue.
The atypical guanine-nucleotide exchange factor, Dock7, negatively regulates Schwann cell differentiation and myelination.
Neurosci. 31, 12579-12592 (2011)
Lethal adulthood myelin breakdown by oligodendrocyte-specific Ddx54 knockout.
iScience. 26, 107448 (2023) * equally contributed
2.Yuki Miyamoto, Tomohiro Torii, Keiichi Homma, Hiroaki Oizumi, Katsuya Ohbuchi, Kazushige Mizoguchi,
Shou Takashima, and Junji Yamauchi.The adaptor SH2B1 and the phosphatase PTP4A1 regulate the phosphorylation of cytohesin-2 in myelinating Schwann cells in mice.
Sci. Signal. 15(3), eabi5276 (2022)
3.Yuki Miyamoto*, Tomohiro Torii, Miho Terao, Shuji Takada, Akito Tanoue, Hironori Katoh, and
Junji Yamauchi.
Rnd2 differentially regulates oligodendrocyte myelination at different developmental periods.
Mol. Biol. Cell 32, 769-787 (2021): *Corresponding author
4.Takahiro Kitahara, Hideya Sakaguchi*, Asuka Morizane, Tetsuhiro Kikuchi, Susumu Miyamoto, Jun
Takahashi*.Axonal extensions along corticospinal tracts from transplanted human cerebral organoids.
Stem Cell Reports. Aug 11;15(2):467-481 (2020) *Corresponding author
5.Yuki Miyamoto, Marina Tanaka, Hisanaka Ito, Hiroaki Ooizumi, Katsuya Ohbuchi, Kazushige Mizoguchi, Tomohiro Torii, and Junji Yamauchi.
Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice.
Biochem. Biophys. Res. Commun. 531, 445-451 (2020)
6.Hideya Sakaguchi*, Yuki Ozaki, Tomoka Ashida, Takayoshi Matsubara, Naotaka Oishi, Shunsuke Kihara, Jun Takahashi*. Self-organized synchronous calcium transients in a cultured human neural network derived from cerebral organoids. Stem Cell Reports. 13(3):458-473 (2019) *Corresponding author
7.Tsutomu Sawai*, Hideya Sakaguchi*, Elizabeth Thomas, Jun Takahashi, Misao Fujita. The ethics of cerebral organiod research: Being conscious of consciousness. Stem Cell Reports.13(3):440-447 (2019) *Corresponding author
8.Takenori Ogura†, Hideya Sakaguchi†*, Susumu Miyamoto, Jun Takahashi J*.
Three-dimensional induction of dorsal, intermediate and ventral spinal cord tissues from human pluripotent stem cells. Development.145(16):dev162214. (2018) *Corresponding author †: co-first author
9.Yuki Miyamoto, Tomohiro Torii, Kenji Tago, Akito Tanoue, Shou Takashima, and Junji Yamauchi.
BIG1/Arfgef1 and Arf1 regulate the initiation of myelination by Schwann cells in mice.
Sci. Adv. 4, eaar4471 (2018)
10.Yuki Miyamoto, Tomohiro Torii, Akito Tanoue, and Junji Yamauchi.
VCAM1 acts in parallel with CD69 and is required for the initiation of oligodendrocyte myelination.
Nat. Commun. 7, 13478 (2016)
11.Hideya Sakaguchi*, Taisuke Kadoshima, Mika Soen, Nobuhiro Narii, Yoshihito Ishida, Masatoshi Ohgushi, Jun Takahashi, Mototsugu Eiraku*, Yoshiki Sasai. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun. Nov 17;6:8896 (2015) *Corresponding author
12.Yuki Miyamoto, Tomohiro Torii, Shuji Takada, Nobuhiko Ohno, Yurika Saitoh, Kazuaki Nakamura,
Akihito Ito, Toru Ogata, Nobuo Terada, Akito Tanoue, and Junji Yamauchi.
Involvement of the Tyro3 receptor and its intracellular partner Fyn signaling in Schwann cell myelination.
Mol. Biol. Cell 26, 3489-3503 (2015)
13.Yuki Miyamoto, Natsuki Yamamori, Tomohiro Torii, Akito Tanoue, and Junji Yamauchi. Rab35, acting through ACAP2 switching off Arf6, negatively regulates oligodendrocyte differentiation and myelination.
Mol. Biol. Cell 25, 1532-1542 (2014)
14.Taisuke Kadoshima, Hideya Sakaguchi, Tokushige Nakano, Mika Soen, Satoshi Ando, Mototsugu Eiraku,
Yoshiki Sasai. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A. 110(50):20284-20289 (2013)15.Fabrizio Piazza, Steven M Greenberg, Mario Savoiardo, Margherita Gardinetti, Luisa Chiapparini, Irina Raicher, Ricardo Nitrini, Hideya Sakaguchi, Monica Brioschi, Giuseppe Billo, Antonio Colombo, Francesca Lanzani, Giuseppe Piscosquito, Maria Rita Carriero, Giorgio Giaccone, Fabrizio Tagliavini, Carlo Ferrarese, Jacopo C DiFrancesco. Anti-Aβ autoantibodies in Cerebral Amyloid Angiopathy-related inflammation: implications for amyloid-modifying therapies.
Ann. Neurol. 73(4):449-458 (2013)
16.Yuki Miyamoto, Tomohiro Torii, Natsuki Yamamori, Toru Ogata, Akito Tanoue, and Junji Yamauchi.
Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons.
Sci. Signal. 6, ra15 (2013)
17.Hideya Sakaguchi*, Satoshi Yamashita, Teruyuki Hirano, Makoto Nakajima, En Kimura, Yasushi Maeda, Makoto Uchino. Myasthenic crisis patients who require intensive care unit management. Muscle & Nerve 46:440-442 (2012) *Corresponding author
18.Junji Yamauchi, Yuki Miyamoto, Tomohiro Torii, Shou Takashima, Kazumi Kondo, Katsumasa Kawahara,
Noriko Nemoto, Jonah R. Chan, Gozoh Tsujimoto, and Akito Tanoue. Phosphorylation of cytohesin-1 by Fyn is required for initiation of myelination and the extent of myelination during development. Sci. Signal. 5, ra69 (2012)19.Yuki Miyamoto, Tomohiro Torii, Akito Tanoue, and Junji Yamauchi.
Pelizaeus-Merzbacher disease-associated proteolipid protein 1 inhibits oligodendrocyte precursor cell differentiation via extracellular-signal regulated kinase signaling.
Biochem. Biophys. Res. Commun. 424, 262-268 (2012)
20.Hideya Sakaguchi*, Akihiko Ueda, Takayuki Kosaka, Satoshi Yamashita, En Kimura, Taro Yamashita, Yasushi Maeda, Teruyuki Hirano, Makoto Uchino. Cerebral amyloid angiopathy-related inflammation presenting with steroid-responsive higher brain dysfunction: case report and review of the literature. J. Neuroinflammation 8:116 (2011) *Corresponding author
21.Hideya Sakaguchi, Satoshi Yamashita, Akiko Miura, Tomoo Hirahara, En Kimura, Yasushi Maeda, Tadashi Terasaki, Teruyuki Hirano, Makoto Uchino. A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot-Marie-Tooth disease. J. Neurol. 258:284-90 (2011)
22.Junji Yamauchi, Yuki Miyamoto, Hajime Hamasaki, Atsushi Sanbe, Shinji Kusakawa, Akane Nakamura, Hideki Tsumura, Masahiro Maeda, Noriko Nemoto, Katsumasa Kawahara, Tomohiro Torii, and Akito Tanoue.
The atypical guanine-nucleotide exchange factor, Dock7, negatively regulates Schwann cell differentiation and myelination.
Neurosci. 31, 12579-12592 (2011)