Restoration of inner ear gap junction with iPS derived model cell and genome editing
| Project/Area Number |
17H04348
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
美野輪 治 順天堂大学, 医学部, 准教授 (00181967)
井下 綾子 順天堂大学, 医学部, 准教授 (00514762)
神谷 和作 順天堂大学, 医学部, 准教授 (10374159)
安齋 崇 順天堂大学, 医学部, 助教 (20624852)
赤松 和土 順天堂大学, 医学(系)研究科(研究院), 教授 (60338184)
飯塚 崇 順天堂大学, 医学部, 非常勤助教 (40372932)
城所 淑信 順天堂大学, 医学部, 助手 (60514487)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2019: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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| Keywords | 遺伝性難聴 / iPS細胞 / ギャップ結合 / GJB2 / ゲノム編集 / 内耳 / 遺伝子改変動物 |
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| Outline of Final Research Achievements |
Mutation of the Gap Junction Beta 2 gene (GJB2) is the most frequent cause of hereditary deafness worldwide and accounts for up to 50% of non-syndromic sensorineural hearing loss. In this study, we examined various adeno associated virus (AAV) serotypes to develop the effective gene therapy for GJB2 related hearing loss. For the disease modeling, we developed a novel strategy to differentiate induced pluripotent stem (iPS) cells into functional CX26-GJP-forming cells that exhibit physiological properties typical of the developing cochlea. To establish the disease model cells from the patients, we generated human iPS cells from the patients with Japanese and East Asian typical GJB2 mutations. As animal models for these typical GJB2 mutations, CRSPR/Cas9 based genome editing were used to establish the mouse model such as GJB2-V37I mutant mouse. These model cells, vectors and animal models will enable us to develop the drugs and gene therapy vectors for GJB2 related hearing loss.
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| Academic Significance and Societal Importance of the Research Achievements |
本課題はこれまでの当グループの研究成果をさらに発展させ、新たな疾患モデル細胞、疾患モデル動物、遺伝子治療ベクター等を開発することにより、根本的治療の存在しなかった遺伝性難聴への遺伝子治療と細胞治療が応用可能であることを示す結果が得られた。ギャップ結合の障害は加齢性難聴の進行に関与することが我々の論文で示されたが、加齢性難聴は認知症のリスクファクターとして最も重要な疾患であることが近年明らかとなり、本課題の成果が認知症分野へも貢献する社会的意義の高い治療法開発であると考えられる。
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Report
(4 results)
Research Products
(12 results)
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[Journal Article] Generation of the induced pluripotent stem cell (hiPSC) line (JUFMDOi004-A) from a patient with hearing loss carrying GJB2 (p.V37I) mutation.2020
Author(s)
Fukunaga I, Shiga T, Chen C, Oe Y, Danzaki K, Ohta S, Matsuoka R, Anzai T, Hibiya-Motegi R, Tajima S, Ikeda K, Akamatsu W, Kamiya K.
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Journal Title
Stem Cell Research
Volume: 4
Related Report
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[Journal Article] Identification of inhibitory mechanisms in pseudo-allergy involving Mrgprb2/MRGPRX2-mediated mast cell activation2019
Author(s)
Takamori A, Ozawa K, Kaitani A, Ando T, Okamoto Y, Maehara A, Tanabe A, Nagamine M, Yamada H, Uchida S, Uchida K, Isobe M, Hatayama T, Watanabe D, Ando T, Ide T, Matsuzawa M, Maeda K, Nakano N, Tamura N, Ikeda K, Ebihara N, Shimizu T, Ogawa H, Okumura K, Kitaura J
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Journal Title
Journal of Allergy and Clinical Immunology
Volume: 143
Issue: 3
Pages: 1231-1235
DOI
Related Report
Peer Reviewed / Open Access
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