Elucidation of the molecular mechanism of the diabetes in Wolfram syndrome

• Project/Area Number: 18K06972
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Fujita Hidetoshi 東京医科大学, 医学部, 講師 (90571802)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ウォルフラム症候群 / シノビオリン / 小胞体ストレス / β細胞 / インスリン分泌 / β 細胞 / インスリン / 糖尿病

Outline of Final Research Achievements

Wolfram syndrome (WS) is the most common genetic type I Diabetes mellitus. Molecular genetic studies show that 90% of WS patients carry a loss-of-function mutation in the WFS1 gene. It has recently been discovered that downregulation of Synoviolin (SYVN1) has been observed in Wfs1-deficient mice and lymphocytes from patients with WS. However, the downstream pathways involved after the degradation of SYVN1 remain unclear. In this study, we generated and analyze pancreatic β cell-specific SYVN1 knockout mice and found that Syvn1 deficiency in β cells causes insufficient insulin secretion.

Academic Significance and Societal Importance of the Research Achievements

Wolfram 症候群 (ウォルフラム症候群)は、常染色体劣性遺伝性疾患であり、日本における患者数はおよそ200人である。代表的な遺伝性の一型糖尿病であり、いまだその根本的な治療法が確立していない疾患でもある。本研究では、シノビオリンの欠失により、インスリン分泌異常が生じることが認められ、かつ、その下流のシグナルの一端を同定した。これらの結果は、これまで報告されていない新規のインスリン分泌制御機構の発見のみならず、同定した下流のシグナル経路が新たなる治療標的になる可能性が考えられる。

Research Products

• [Journal Article] Grap2 cyclin D interacting protein negatively regulates CREB?binding protein, inhibiting fibroblast?like synoviocyte growth (2021)
  • Author(s): Fujita Hidetoshi、Aratani Satoko、Nakajima Toshihiro
  • Journal Title: Molecular Medicine Reports Volume: 23
  • DOI: 10.3892/mmr.2021.11916
  • Peer Reviewed
• [Journal Article] Enhanced expression of synoviolin in peripheral blood from obese/overweight donors (2020)
  • Author(s): Fujita Hidetoshi、Aratani Satoko、Mizoguchi Izuru、Yagishita Naoko、Nakajima Toshihiro
  • Journal Title: Experimental and Therapeutic Medicine Volume: 20
  • DOI: 10.3892/etm.2020.9249
  • Peer Reviewed
• [Journal Article] Identification of the inhibitory activity of E3 ligase Syvn1 in walnut extract. (2018)
  • Author(s): Fujita H, Aratani S, Yagishita N, Nishioka K, Nakajima T.
  • Journal Title: Mol. Med. Rep Volume: 8(6) Pages: 5701-5708
  • Peer Reviewed / Open Access
• [Journal Article] The NRF2-PGC-1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, Synoviolin, in a cecal ligation/perforation -induced septic mouse model. (2018)
  • Author(s): Ishida Y, Fujita H, Aratani S, Chijiiwa M, Taniguchi N, Yokota M, Ogihara Y, Uoshima N, Nagashima F, Uchino H, Nakajima T.
  • Journal Title: Mol. Med. Rep Volume: 18(2) Pages: 2467-2475
  • Peer Reviewed / Open Access
• [Presentation] 脳内炎症に関わるキヌレニンの代謝機構の解明 (2018)
  • Author(s): 藤田 英俊、石田 裕介、荒谷 聡子、横田 真穂、内野 博之、中島 利博
  • Organizer: 日本線維筋痛症学会第 10 回学術集会
• [Patent(Industrial Property Rights)] ウォルフラム症候群の治療剤 (2019)
  • Inventor(s): 中島、藤田、黒田、金蔵、平本、熊谷、青野
  • Industrial Property Rights Holder: 中島、藤田、黒田、金蔵、平本、熊谷、青野
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-061768
  • Filing Date: 2019