Elucidaion of muscular pathology of SBMA using disease specific iPSCs
Project/Area Number |
19K07969
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 52020:Neurology-related
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Research Institution | Aichi Medical University |
Principal Investigator |
道勇 学 愛知医科大学, 医学部, 教授 (90293703)
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Co-Investigator(Kenkyū-buntansha) |
岡田 洋平 愛知医科大学, 加齢医科学研究所, 教授 (30383714)
伊藤 卓治 愛知医科大学, 加齢医科学研究所, 助教 (30794151)
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Project Period (FY) |
2019-04-01 – 2024-03-31
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Project Status |
Completed (Fiscal Year 2023)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | 疾患iPS細胞 / 球脊髄性筋萎縮症 / 骨格筋 / トランスクリプトーム / iPS細胞 |
Outline of Research at the Start |
球脊髄性筋萎縮症(SBMA)は、30-50歳代の男性に発症する緩徐進行性の下位運動ニューロン変性疾患である。従来は運動ニューロンに着目した解析がほとんどであったが、近年、骨格筋そのもの、あるいは骨格筋による運動ニューロンへの非細胞自律的な病態が示唆されている。しかし、その存在を直接的に示した報告はなく、またその詳細な分子機序は未解明である。本研究では、SBMA疾患iPS細胞由来骨格筋における病態変化と、その背景にある分子メカニズムを解明する。また、この骨格筋病態が運動ニューロンに及ぼす影響をiPS細胞による神経・筋共培養システムを用いて明らかにする。
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Outline of Annual Research Achievements |
(1) iPS由来骨格筋の分化誘導と成熟度・機能性評価システムの開発:これまでに開発した培養法を改良し、ヒトiPS細胞から簡便・迅速・高効率に骨格筋を誘導する培養法を確立した。さらに、この方法で誘導した骨格筋を三次元で培養し、筋収縮を得ることに成功した。さらに、複数の化合物を添加してシグナルを制御することで、より成熟した骨格筋を得ることに成功している。 (2) SBMA患者iPS細胞由来骨格筋における病態解析:SBMA患者、および健常者iPS細胞から骨格筋への分化誘導を行い、疾患表現型を解析した。その結果、細胞死、成熟度などについては大きな病態変化が観察されなかったが、骨格筋分化に関与する複数の遺伝子発現変化や速筋の減少など、これまでに報告されている複数の病態変化が観察された。 (3) 患者iPS由来骨格筋の病態関連因子の探索:候補アプローチによる遺伝子発現変化を行ったところ、患者由来骨格筋で病態変化を示す分子を複数同定した。さらに、トランスクリプトーム解析を行い、病態に関与すると考えられる複数の分子を同定し、その解析を進めている。
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Report
(5 results)
Research Products
(71 results)
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[Journal Article] An Exploratory Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS): Protocol for a Multicenter, Open-Labeled, 24-Week, Single-Group Study.2023
Author(s)
Haji S, Fujita K, Oki R, Osaki Y, Miyamoto R, Morino H, Nagano S, Atsuta N, Kanazawa Y, Matsumoto Y, Arisawa A, Kawai H, Sato Y, Sakaguchi S, Yagi K, Hamatani T, Kagimura T, Yanagawa H, Mochizuki H, Doyu M, Sobue G, Harada M, Izumi Y.
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Journal Title
JMIR Res Protoc.
Volume: 12
Pages: e42032-e42032
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[Journal Article] The SYNGAP1 3'UTR variant in ALS patients causes aberrant SYNGAP1 splicing and dendritic spine loss by recruiting HNRNPK2022
Author(s)
Yokoi S, Ito T, Sahashi K, Nakatochi M, Tohnai G, Nakamura R, Fujioka Y, Ishigaki S, Udagawa T, Izumi Y, Morita M, Kano O, Oda M, Sone T, Okano H, Atsuta N, Katsuno M, Okada Y*, Sobue G*
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Journal Title
Journal of Neuroscience
Volume: 42
Issue: 47
Pages: 8881-8896
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[Journal Article] Two distinct mechanisms of neuropathy in immunoglobulin light chain (AL) amyloidosis2021
Author(s)
Koike H, Mouria N, Fukamia Y, Iijima M, Matsuo K, Yagi N, Saito A, Nakamura H, Takahashi K, Nakae Y, Okada Y, Tanaka F, Sobue G, Katsuno M
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Journal Title
Commun Biol.
Volume: 421
Pages: 117305-117305
DOI
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[Journal Article] Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS.2021
Author(s)
Hirunagi T, Sahashi K, Tachikawa K, Leu AI, Nguyen M, Mukthavaram R, Karmali PP, Chivukula P, Tohnai G, Iida M, Onodera K, Ohyama M, Okada Y, Okano H, Katsuno M.
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Journal Title
Mol Ther Nucleic Acids.
Volume: 24
Pages: 1-10
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[Journal Article] Antiparkinsonian drugs as potent contributors to nocturnal sleep in patients with Parkinson's disease.2021
Author(s)
Taguchi S, Koide H, Oiwa H, Hayashi M, Ogawa K, Ito C, Nakashima K, Yuasa T, Yasumoto A, Ando H, Fujikake A, Fukuoka T, Tokui K, Izumi M, Tsunoda Y, Kawagashira Y, Okada Y, Niwa JI, Doyu M.
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Journal Title
PLoS One.
Volume: 16
Issue: 7
Pages: e0255274-e0255274
DOI
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[Journal Article] Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs2020
Author(s)
Onodera K, Shimojo D, Ishihara Y, Yano M, Miya F, Banno H, Kuzumaki N, Ito T, Okada R, Ohyama M, Yoshida M, Tsunoda T, Katsuno M, Doyu M, Sobue G, Okano H, Okada Y
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Journal Title
Mol. Brain
Volume: 13
Issue: 1
Pages: 18-18
DOI
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[Journal Article] Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons.2019
Author(s)
Akiyama T, Suzuki N, Ishikawa M, Fujimori K, Sone T, Kawada J, Funayama R, Fujishima F, Mitsuzawa S, Ikeda K, Ono H, Shijo T, Osana S, Shirota M, Nakagawa T, et al.
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Journal Title
EBioMedicine
Volume: 45
Pages: 362-378
DOI
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[Journal Article] Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy2019
Author(s)
Iida M, Sahashi K, Kondo N, Nakatsuji H, Tohnai G, Tsutsumi Y, Noda S, Murakami A, Onodera K, Okada Y, Nakatochi M, Okabe Y, Shimizu S, Mizuno M, Adachi H, Okano H, Sobue G, Katsuno M
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Journal Title
Nat. Commun.
Volume: 10
Pages: 4262-4262
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[Journal Article] Tandem paired nicking promotes precise genome editing with scarce interference by p532019
Author(s)
Hyodo T, Rahman ML, Karnan S, Ito T, Toyoda A, Ota A, Wahiduzzaman M, Tsuzuki S, Okada Y, Hosokawa Y, Konishi H.
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Journal Title
Cell Rep.
Volume: 30
Issue: 4
Pages: 1195-1207
DOI
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Peer Reviewed / Open Access
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[Presentation] Elucidating early pathophysiology of spinal-bulbar muscular atrophy using disease-specific iPSCs2023
Author(s)
小野寺 一成, 下門 大祐, 石原 康晴, 太田 明伸, 宮 冬樹, Rashid Muhammad Irfanur, 伊藤 卓治, 岡田 梨奈, 細川 好孝, 道勇 学, 祖父江 元, 勝野 雅央, 岡野 栄之, 岡田 洋平
Organizer
第64回日本神経学会学術大会
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[Presentation] Exploration of pathogenic molecules in motor neuron disease using the human ipsc-derived neuromuscular model2023
Author(s)
Ito T, Rashid MI, Onodera K, Okada R, Shimojo D, Tanaka S, Katsuno M, Sobue G, Doyu M, Okano H, Okada Y
Organizer
第46回日本分子生物学会年会
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[Presentation] Establishment of a more efficient disease model for ALS using feeder-free disease specific iPSCs2023
Author(s)
Khatun Z, Onodera K, Yamaguchi S, Okada R, Ito T, Rashid MI, Inoue H, Aoki M, Okano H, Doyu M, Okada Y
Organizer
第46回日本分子生物学会年会
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[Presentation] Phase 3b extension study to evaluate the efficacy and safety of 2 dosing regimens of oral edaravone in patients with amyotrophic lateral sclerosis2023
Author(s)
Rothstein J, De Silva S, Zinman L, Chum M, Chio A, Ludolph AC, Sobue G, Doyu M, Selness D, Todorovic V, Hirai M, Takahashi F, Sakata T, Wamil A, Salah A, Apple S
Organizer
148th Annual Meeting American-Neurological-Association (ANA)
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[Presentation] Phase 3B extension study evaluating superiority of daily vs approved on/off oral edaravone dosing in patients with amyotrophic lateral sclerosis2023
Author(s)
Rothstein J, Desilva S, Zinman L, Chum M, Chio A, Ludolph AC, Sobue G, Doyu M, Selness D, Todorovic V, Hirai M, Takahashi F, Wamil A, Salah A, Apple S
Organizer
22nd Annual Meeting of the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS)
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[Presentation] Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients2023
Author(s)
Nakamura R, Tohnai G, Nakatochi M, Niwa JI, Doyu M, Fujimori K, Morimoto S, Okada Y, Okano H, Sobue G et al.,
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34th international symposium on ALS/MND
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[Presentation] Phase 3B extension study evaluating superiority of daily vs approved on/off oral edaravone dosing in patients with amyotrophic lateral sclerosis2023
Author(s)
Rothstein J, Desilva S, Zinman L, Chum M, Chio A, Ludolph AC, Sobue G, Doyu M, Selness D, Todorovic V, Hirai M, Takahashi F, Wamil A, Salah A, Apple S
Organizer
26th World Congress of Neurology (WCN)
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[Presentation] Phase 3B study evaluating superiority of daily dosing vs approved on/off oral edaravone dosing over 48 weeks in patients with amyotrophic lateral sclerosis (MT-1186-A02)2023
Author(s)
Salah A, Desilva S, Zinman L, Chum M, Chio A, Ludolph AC, Sobue G, Doyu M, Selness D, Todorovic V, Hirai M Wamil A, Apple S
Organizer
26th World Congress of Neurology (WCN)
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[Presentation] Elucidating early pathophysiology of spinal-bulbar muscular atrophy using disease-specific iPSCs2022
Author(s)
小野寺一成, 下門大祐, Bruno De Araujo Herculano1, 石原康晴, 依田真由子, 太田明伸, 矢野真人, 宮冬樹, Rashid Muhammad Irfanur, 伊藤卓治, 岡田梨奈, 角田達彦, 細川好孝, 道勇学, 祖父江元, 勝野雅央,岡野栄之,岡田洋平
Organizer
第63回日本神経学会学術大会
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[Presentation] Establishment of a more efficient disease model for ALS using feeder-free disease specific iPSCs2022
Author(s)
Khatun Z, Onodera K, Yamaguchi S, Okada R, Ito T, Rashid MI, Inoue H, Aoki M, Okano H, Doyu M, Okada Y
Organizer
第33回日本末梢神経学会学術集会
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[Presentation] Establishment of a more efficient disease model for ALS using feeder-free disease specific iPSCs2022
Author(s)
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Organizer
第45回日本分子生物学会年会
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[Presentation] Bulk differentiation of iPSCs into contractible muscles for muscular disease modeling2022
Author(s)
Rashid MI, Ito T, Miya F, Shimojo D, Arimoto K, Onodera K, Okada R, Nagashima T, Yamamoto K, Khatun Z, Okano H, Sakurai H, Shimizu K, Doyu M, Okada Y
Organizer
第45回日本分子生物学会年会
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[Presentation] Establishment of a more efficient disease model for ALS using feeder-free disease specific iPSCs2022
Author(s)
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第22回日本再生医療学会総会
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[Presentation] Elucidating early pathophysiology of spinal-bulbar muscular atrophy using disease-specific iPSCs2021
Author(s)
小野寺一成, 下門大祐, de Ara?jo Herculano B,石原康晴, 依田真由子, 太田明伸, 矢野真人, 宮冬樹, Rashid MI, 伊藤卓治, 岡田梨奈, 角田達彦, 細川好孝, 道勇学, 祖父江元, 勝野雅央, 岡野栄之, 岡田 洋平
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第62回日本神経学会学術大会
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[Presentation] 脳卒中患者における自律神経機能と病状との関連2021
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中島 康自, 小出 弘文, 林 未久, 伊藤 千弘, 湯淺 知子, 安本 明弘, 安藤 宏明, 田口 宗太郎, 藤掛 彰史, 福岡 敬晃, 徳井 啓介, 川頭 祐一, 岡田 洋平, 丹羽 淳一, 道勇 学
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第62回日本神経学会学術大会
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[Presentation] Allele selective suppression of mutant polyQ protein by LNP-delivered siRNA targeting CAG expansions2021
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蛭薙智紀, 佐橋健太郎, 立川潔, Leu A, Nguyen M, Mukthavaram R, Karmali P, Chivukula P, 藤内玄規, 飯田円, 小野寺一成, 大山学, 岡田 洋平, 岡野栄之, 勝野雅央
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第62回日本神経学会学術大会
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[Presentation] Elucidating early pathophysiology of Spinal-bulbar muscular atrophy using diseasespecific iPSCs.2021
Author(s)
Onodera K, Shimojo D, de Ara?jo Herculano B, Ishihara Y, Yoda M, Ota A, Rashid MI, Ito T, Okada R, Hosokawa Y, Doyu M, Sobue G, Katsuno M, Okano H, Okada Y
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ISSCR/JSRM 2021 Tokyo International Symposium, Tokyo
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[Presentation] 疾患iPS細胞による神経・筋共培養を活用した神経変性疾患の病態解析2020
Author(s)
伊藤卓治, 小野寺一成, 小野寺一成, 下門大祐, 下門大祐, 田中智史, 田中智史, 岡田梨奈, RASHID Muhammad Irfanur, 道勇学, 岡野栄之, 岡田洋平
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