Elucidation of early pathology of motor neuron diseases using disease specific iPSCs
Project/Area Number |
19H03576
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 52020:Neurology-related
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Research Institution | Aichi Medical University |
Principal Investigator |
Okada Yohei 愛知医科大学, 加齢医科学研究所, 教授 (30383714)
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Co-Investigator(Kenkyū-buntansha) |
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 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2021: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2020: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
|
Keywords | 疾患iPS細胞 / 運動ニューロン疾患 / 早期病態 |
Outline of Research at the Start |
球脊髄性筋萎縮症(SBMA)は、30~50歳台の成人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。ポリグルタミン鎖の伸長した変異ARが、リガンドであるテストステロン依存的に凝集体を形成し、神経変性を誘導すると考えられてきた。一方で、変異AR凝集体によらない早期病態が示唆されており、またリュープロレリン(抗アンドロゲン療法)は発症早期の患者でのみ有効性が示されたことから、早期病態の解明と早期治療は必要不可欠である。本研究では、SBMA疾患iPS細胞による早期病態モデルを用いて同定した4つの分泌型神経ペプチドに着目し、SBMAの早期病態、神経・筋病態解明と新規治療標的の探索を行う。
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Outline of Final Research Achievements |
Spinal bulbar muscular atrophy (SBMA) is an adult-onset motor neuron degenerative disease. Previous analysis has shown the pathogenesis induced by mutant androgen receptor (AR) aggregates, however, recent analysis suggested pathology independent of mutant AR aggregates. Moreover, leuprorelin treatment has shown to be effective especially in patients in the early stage of the disease. In this study, we generated an early disease model using motor neurons derived from SBMA disease-specific iPSCs, and identified molecules that were involved in the early pathology of SBMA. Inhibitors of the identified molecules and their downstream molecules rescued the phenotype, suggesting that these molecules could be novel therapeutic targets of SBMA.
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Academic Significance and Societal Importance of the Research Achievements |
本研究により、SBMA疾患特異的iPS細胞を用いることで、SBMAの早期病態を再現し得る病態モデルを作成し、早期病態に関与する分子を同定することができた。また、これらの分子の病態への関与を解析することで、SBMAの早期病態の一部を解明し、新規治療標的を同定することができた。今後は、同定した分子を足がかりにSBMAの早期病態の詳細を解明するとともに、新規治療開発に向けた解析を進めていく予定である。
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Report
(4 results)
Research Products
(57 results)
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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
DOI
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Peer Reviewed / Open Access
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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
Related Report
Peer Reviewed
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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
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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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
Related Report
Peer Reviewed / Open Access
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[Journal Article] A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.2020
Author(s)
Nakamura R, Misawa K, Tohnai G, Nakatochi M, Furuhashi S, Atsuta N, Hayashi N, Yokoi D, Watanabe H, Watanabe H, Katsuno M, Izumi Y, Kanai K, Hattori N, Morita M, Taniguchi A, Kano O, Oda M, Shibuya K, Kuwabara S, Suzuki N, Aoki M, Ohta Y, Yamashita T, Abe K, Hashimoto R, Aiba I, Okada Y, Nagasaki M, Sobue G. et al.,
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Journal Title
Commun Biol.
Volume: 23
Issue: 1
Pages: 526-526
DOI
NAID
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Peer Reviewed / Open Access
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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
Related Report
Peer Reviewed / Open Access
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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
Related Report
Peer Reviewed / Open Access
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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
Related Report
Peer Reviewed / Open Access
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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
Related Report
Peer Reviewed / Open Access
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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)
Khatun Z, Onodera K, Yamaguchi S, Okada R, Ito T, Rashid MI, Inoue H, Aoki M, Okano H, Doyu M, Okada Y
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)
Khatun Z, Onodera K, Yamaguchi S, Okada R, Ito T, Rashid MI, Inoue H, Aoki M, Okano H, Doyu M, Okada Y
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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
Organizer
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
Author(s)
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
Author(s)
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
Organizer
第62回日本神経学会学術大会
Related Report
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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
Organizer
ISSCR/JSRM 2021 Tokyo International Symposium, Tokyo
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