Mechanism clarification of new symptoms in DFNA1 causing from constitutively active DAI1 mutants
| Project/Area Number |
17H04042
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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 |
General medical chemistry
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| Research Institution | Kobe University |
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Principal Investigator |
Ueyama Takehiko 神戸大学, バイオシグナル総合研究センター, 准教授 (80346254)
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| Co-Investigator(Kenkyū-buntansha) |
坂口 博史 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (00515223)
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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 |
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
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| Keywords | 感音難聴 / DFNA1 / DIAPH1 / DIA1 / 遺伝性難聴 / 進行性難聴 / 血液異常 / 遺伝 / ＤＩＡ１ |
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| Outline of Final Research Achievements |
1. Noise exposure induced significantly decreased number of the ribbon synapse in hair cells in mice expressing a DIA1 mutant (p.R1213X) compared with control mice, suggesting that noise is one of factors leading to progressive hearing loss in DFNA1 patients.
2. In mice expressing the DIA1 mutant, the mutant was localized at the apical junctional complex (AJC) of hair cells, where showed morphological abnormalities by TEM. Thus, AJC is likely the main lesion in DFNA1.
3. In aged mice expressing the DIA1 mutant, size of the platelets was spread over a wider range, compared with control mice. Detailed studies analyzing the mechanism manifesting the phenotype are going on.
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| Academic Significance and Societal Importance of the Research Achievements |
遺伝性感音難聴の一病型であるDFNA1の進行性難聴の発症機序を解明した。1. 主要病変部位は、変異体が局在する蝸牛有毛細胞の頂側結合である、2. 騒音により有毛細胞内のリボンシナプス数が減少する。
これらは、DFNA1の治療戦略上、大きな成果である。現在、引き続きDFNA1の治療薬開発を進めているが、本研究の継続・成功により、有効な治療薬のない感音難聴の治療法開発の扉を開けることが出来ると確信している。
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Report
(4 results)
Research Products
(19 results)
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[Journal Article] Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 142018
Author(s)
Nakazono, A., Adachi, N., Takahashi, H., Seki, T., Hamada, D., Ueyama, T., Sakai, N. and Saito, N.
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Journal Title
J. Biol. Chem.
Volume: 293
Issue: 38
Pages: 14758-14774
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The Role of Cysteine String Protein Alpha (CSPα) Phosphorylation at Serine 10, and 34, by Protein Kinase Cγ for Presynaptic Maintenance.2018
Author(s)
Shirafuji T, Ueyama T, Adachi N, Yoshino KI, Sotomaru Y, Uwada J, Kaneoka A, Ueda T, Tanaka S, Hide I, Saito N, Sakai N
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Journal Title
J. Neurosci.
Volume: 38
Issue: 2
Pages: 278-290
DOI
Related Report
Peer Reviewed
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[Journal Article] Novel role of Rac-Mid1 signaling in medial cerebellar development.2017
Author(s)
Nakamura T, Ueyama T, Ninoyu Y, Sakaguchi H, Choijookhuu N, Hishikawa Y, Kiyonari H, Kohta M, Sakahara M, de Curtis I, Kohmura E, Hisa Y, Aiba A, Saito N.
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Journal Title
Development
Volume: 144
Issue: 10
Pages: 1863-1875
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Validation of Anti-CSPα, SNAP25, Tyrosine Hydroxylase, Ubiquitin, Cleaved Caspase 3, and pSer PKC Motif Antibodies for Utilization in Western Blotting2017
Author(s)
Shirafuji T, Ueyama T, Tanaka S, Hide I, Saito N and Sakai N
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Journal Title
ACTA HISTOCHEMICA ET CYTOCHEMICA
Volume: 50
Issue: 6
Pages: 177-180
DOI
NAID
ISSN
0044-5991, 1347-5800
Related Report
Peer Reviewed / Open Access
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