| Project/Area Number |
18K16236
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
TSOUMPRA MARIA 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 遺伝子疾患治療研究部, 科研費研究員 (80756198)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | vitamin D / vitamin D receptor / dystrobrevin / dystrophin / muscular dystrophy / muscle / vitamin D3 / dystrobrevin alpha / myogenic differentiation |
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| Outline of Final Research Achievements |
The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response elements (VDRE) and activate target genes. We have elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a protein homologue of dystrophin. In healthy and dystrophic murine-derived myogenic cells, Dtna and Vdr gene and protein expression were upregulated by VD3 in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we validated a VDRE site in Dtna murine muscle-specific promoter and proved that the positive regulation of Dtna by VD3 is VDR-mediated and specific. Our study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in treatments aiming to stabilize dystrophin in musculoskeletal diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
VD3投与により、マウスの骨格筋細胞の筋原性因子の転写調節とともにVDRの発現亢進がおこることから、VD3は筋肉に有益な作用を有すると想定される。これまでにもVD3の筋肉に対する作用は報告されていたものの、その機序や標的遺伝子には不明な点が残されていた。本研究により、VDR依存性のDtna発現調節機構が明らかとなった。今後Dtnaの筋肉における詳細な機能や作用機序を明らかにすることにより、本成果は骨格筋疾患においてジストロフィン結合蛋白複合体を安定化させることを目的とする治療の開発に役立つ可能性がある
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