Implication of Synoviolin on Limb-Girdles Muscle Dystrophy.

• Project/Area Number: 15K15091
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical University
• Principal Investigator: NAKAJIMA TOSHIHIRO 東京医科大学, 医学部, 教授 (90260752)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 分子病理学 / 筋ジストロフィー / 創薬開発 / タンパク質分解系 / ユビキチン / 分子病態学

Outline of Final Research Achievements

The functional discrepancy in missense mutation between in vitro and in vivo remains to be uncovered. To explain this observation, protein degradation system has been interested. For example, type2 Limb-Girdle Muscle dystrophy is known to be caused by missense mutant of α-sarcoglycan gene. The missense mutant type protein has approximately 30% of residual activity in vitro but the protein is not detected in cell, and Synoviolin plays a crucial role in the degradation of missense α-sarcoglycan protein.
To develop the innovative therapy, we attempted to understand the physiological and pathological role of Synoviolin. By using muscle-specific its knock out mice, we found the gene plays an important role in muscle. We previously developed Synoviolin inhibitor and this inhibitor had protective effect on muscle atrophy model. These two data clearly indicate Synoviolin as a therapeutic target of muscle diseases including Limb-Girdle muscle dystrophy and muscle atrophy.

Research Products

• [Journal Article] Inhibitory effects of ubiquitination of synoviolin by PADI4. (2017)
  • Author(s): Aratani S, Fujita H, Yagishita N, Yamano Y, Okubo Y, Nishioka K, Nakajima T
  • Journal Title: Mol. Med. Rep Volume: in press
  • Peer Reviewed
• [Journal Article] A Study of Brain Metabolism in Fibromyalgia by Positron Emission Tomography (2017)
  • Author(s): Usui C, Soma T, Hatta K, Aratani S, Fujita H, Nishioka K, Machida Y, Kuroiwa Y, Nakajima T, Nishioka K
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry. Volume: 75 Pages: 120-127
  • DOI: 10.1016/j.pnpbp.2017.01.012
  • Peer Reviewed / Open Access
• [Journal Article] Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin (2016)
  • Author(s): Aratani S, Fujita H, Kuroiwa Y, Usui C, Yokota S, Nakamura I, Nishioka K, Nakajima T
  • Journal Title: Sci.Rep Volume: 6 Issue: 1 Pages: 36943-36943
  • DOI: 10.1038/srep36943
  • Peer Reviewed / Open Access
• [Journal Article] Notch2 signaling regulates the proliferation of murine bone marrow-derived mesenchymal stem/stromal cells via c-Myc expression. (2016)
  • Author(s): Yukio S, Mabuchi Y, Miyamoto K, Araki D, Niibe K, Houlihan DD, Morikawa S, Nakagawa T, Nakajima T, Akazawa C, Hori S, Okano H, Matsuzaki Y
  • Journal Title: PLOS ONE Volume: 11（11） Issue: 11 Pages: 0165946-0165946
  • DOI: 10.1371/journal.pone.0165946
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A case of fibromyalgia involving pain throughout the body treated with site-specific targeted pain control. (2016)
  • Author(s): Nakajima F, Aratani S, Fujita H, Nakatani K, Makita K, Nakajima T
  • Journal Title: Springerplus Volume: 5 Issue: 1 Pages: 1027-1027
  • DOI: 10.1186/s40064-016-2572-z
  • Peer Reviewed / Open Access
• [Journal Article] NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of homocysteine-inducible endoplasmic reticulum protein. (2016)
  • Author(s): Maeda T, Tanabe-Fujimura C, Fujita Y, Abe C, Nanakida Y, Kun Zou, Liu J, Liu S, Nakajima T, Komano H
  • Journal Title: Biochem Biophys Res Commun Volume: 473（4） Pages: 1276-1280
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Adverse effects of human papolloma virus vaccination on central nervous system:Neuro-endocrinological disorders of hypothalamo-pituitary axis. (2016)
  • Author(s): Hirai T,Kuroiwa Y,Hayashi T,Uchiyama M,Nakamura I,Yokota S, Nakajima T, Iguchi Y
  • Journal Title: The Autonomic Nervous System Volume: 53（1） Pages: 49-64
  • Peer Reviewed
• [Journal Article] Mitochondrial Ubiquitin Ligase Activator of NF-κB (MULAN) regulates NF-κB signaling in ER stress-stimulated cells. (2016)
  • Author(s): Fujita H, Aratani S, Fujii R, Yamano Y, Yagishita N, Araya N, Izumi T, Azakami K, Hasegawa D, Nishioka K and Nakajima T
  • Journal Title: Int J Mol Med. Volume: 37 Issue: 6 Pages: 1611-1618
  • DOI: 10.3892/ijmm.2016.2566
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1β. (2015)
  • Author(s): Fujita H, Yagishita N, Aratani S, Saito-Fujita T, Morota S, Yamano Y, Hansson MJ, Inazu M, Kokuba H, Sudo K, Sato E, Kawahara K, Nakajima F, Hasegawa D, Higuchi I, Sato T, Araya N, Usui C, Nishioka K, Nakatani Y, Maruyama I, Usui M, Hara N, Uchino H, Elmer E, Nishioka K, Nakajima T.
  • Journal Title: EMBO J. Volume: 34 Issue: 8 Pages: 1042-55
  • DOI: 10.15252/embj.201489897
  • Peer Reviewed / Open Access
• [Presentation] 関節リウマチにおける転写後修飾による多重化シグナル調節機構の解析。 (2016)
  • Author(s): 荒谷聡子、藤田英俊、八木下尚子、山野嘉久、西岡久寿樹、中島利博
  • Organizer: 第 3 回 JCR ベーシックリサーチカンファレンス
  • Place of Presentation: アキバホール(東京 千代田区）
  • Year and Date: 2016-10-14
• [Presentation] リウマチ発症因子シノビオリンによる新規エネルギー代謝機構の解明。 (2016)
  • Author(s): 藤田英俊、荒谷聡子、八木下尚子、山野嘉久、須藤カツ子、内野博之、西岡久寿樹、中島利博
  • Organizer: 第 3 回 JCR ベーシックリサーチカンファレンス
  • Place of Presentation: アキバホール(東京 千代田区）
  • Year and Date: 2016-10-14
• [Presentation] シノビオリンが拓く慢性炎症・関節リウマチの病態メカニズムと新規治療法の開発。 (2016)
  • Author(s): 中島利博
  • Organizer: 第 31 回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡国際会議場(福岡県 福岡市)
  • Year and Date: 2016-10-13
• [Presentation] シノビオリン阻害剤の探索。 (2016)
  • Author(s): 藤田英俊、荒谷聡子、西岡久寿樹、中島利博
  • Organizer: 日本線維筋痛症学会第 8 回学術集会
  • Place of Presentation: KFC Hall & Rooms(東京 墨田区)
  • Year and Date: 2016-09-17
• [Presentation] マウスモデルを用いたシノビオリン阻害活性を有する天然物の効果の検証。 (2016)
  • Author(s): 藤田英俊、荒谷聡子、西岡久寿樹、中島利博
  • Organizer: 日本線維筋痛症学会第 8 回学術集会
  • Place of Presentation: KFC Hall & Rooms(東京 墨田区)
  • Year and Date: 2016-09-17
• [Presentation] ヒトにおけるシノビオリン阻害剤の効果の検証。 (2016)
  • Author(s): 藤田英俊、荒谷聡子、西岡久寿樹、中島利博
  • Organizer: 日本線維筋痛症学会第 8 回学術集会
  • Place of Presentation: KFC Hall & Rooms(東京 墨田区)
  • Year and Date: 2016-09-17
• [Presentation] 新規自己炎症症候群モデルマウスの樹立とシノビオリン阻害剤の効果。 (2016)
  • Author(s): 中島利博
  • Organizer: 第 17 回 運動器科学研究会
  • Place of Presentation: 大阪大学中之島センター（大阪府 大阪市）
  • Year and Date: 2016-09-02
• [Presentation] リウマチ発症因子シノビオリンによるエネルギー代謝調節の解明。 (2016)
  • Author(s): 藤田英俊
  • Organizer: 第17 回 運動器科学研究会
  • Place of Presentation: 大阪大学中之島センター（大阪府 大阪市）
  • Year and Date: 2016-09-02
• [Presentation] シノビオリン阻害剤の実用化に向けて。 (2016)
  • Author(s): 荒谷聡子
  • Organizer: 第 17 回 運動器科学研究会
  • Place of Presentation: 大阪大学中之島センター（大阪府 大阪市）
  • Year and Date: 2016-09-02
• [Presentation] Synoviolin, as a novel factor for understanding obesity and metabolic disorders based on chronic inflammation. (2016)
  • Author(s): Aratani S, Nakajima T
  • Organizer: International Conference on Obesity and Chronic Diseases (ICOCD-2016)
  • Place of Presentation: Las Vegas(USA）
  • Year and Date: 2016-07-25
  • Int'l Joint Research
• [Presentation] E3 Ubiquitin ligase synoviolin inhibitors has effects on obesity. (2016)
  • Author(s): Aratani S, Fujita H, Yagishita N*, Yokota M, Nishioka K, Nakajima T
  • Organizer: International Conference on Obesity and Chronic Diseases (ICOCD-2016)
  • Place of Presentation: Las Vegas(USA）
  • Year and Date: 2016-07-25
  • Int'l Joint Research
• [Presentation] Synoviolin, as a new stellar factor for understanding chronic inflammation. (2016)
  • Author(s): Nakajima T
  • Organizer: MOSCOW INTERNATIONAL FORUM OF BONES AND JOINTS DISORDERS/THE INTERNATIONAL SCHOOL CONFERENCE(ISC)
  • Place of Presentation: Moscow（Russia ）
  • Year and Date: 2016-04-18
  • Int'l Joint Research
• [Presentation] Synoviolin, as a new stellar factor for understanding chronic inflammation (2016)
  • Author(s): Nakajima T
  • Organizer: MOSCOW INTERNATIONAL FORUM OF BONES AND JOINTS DISORDERS/THE INTERNATIONAL SCHOOL CONFERENCE (ISC)
  • Place of Presentation: Moscow, Russia
  • Year and Date: 2016-04-18
  • Int'l Joint Research
• [Presentation] 慢性炎症に関わるシノビオリンの新規エネルギー代謝調節機構 (2015)
  • Author(s): 藤田英俊、荒谷聡子、八木下尚子、須藤カツ子、中島若巳、内野博之、西岡久寿樹、中島利博
  • Organizer: BMB2015 (第38回 日本分子生物学会年会、第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
• [Presentation] Synoviolin and metabolic disorder (2015)
  • Author(s): Nakajima T
  • Organizer: Shanghai-Tokyo Workshop on Rheumatology 2015
  • Place of Presentation: 上海,中国
  • Year and Date: 2015-07-31
  • Int'l Joint Research / Invited
• [Remarks] 東京医科大学医学総合研究所運動器科学研究部門
  • URL: http://toshinakajima2014.wixsite.com/tokyomed
• [Remarks] 東京医科大学 医学総合研究所 運動器科学研究部門
  • URL: http://toshinakajima2014.wix.com/tokyomed