Identification and functional analysis of causative genes for thymoma and muscle atrophy developing in BUF/Mna rats

• Project/Area Number: 15K06812
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Chubu University
• Principal Investigator: ICHIHARA Masatoshi 中部大学, 生命健康科学部, 教授 (00314013)
• Co-Investigator(Kenkyū-buntansha): 村雲 芳樹 北里大学, 医学部, 教授 (40324438) ; 祖父江 沙矢加 中部大学, 臨床検査技術教育・実習センター, 講師 (50513347)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 胸腺腫 / 筋萎縮 / 次世代シークエンス

Outline of Final Research Achievements

The BUF/Mna rat strain is a line susceptible to the spontaneous development of thymoma, muscle atrophy, and glomerulosclerosis. However, the genes responsible for thymoma and muscle atrophy in BUF/Mna rats have not been identified. In this study, we provide the first whole genome sequence of BUF/Mna rats. We compared single nucleotide variants (SNVs) in BUF/Mna of the reference sequence to those of 40 or more inbred rat strains and identified SNVs in genes likely to be related to the development of thymoma and muscle atrophy. We observed that forced expression of the SNV-containing gene correlating with thymoma resulted in morphological alterations of mitochondria as compared to that with wild-type sequence. We also speculate that the causative gene harboring the SNV for muscle atrophy results in a preferential loss of fast-twitch muscle fibers via a sarcopenia-like pathogenic mechanism.

Academic Significance and Societal Importance of the Research Achievements

BUF/Mna系ラットは胸腺腫、筋萎縮、腎糸球体硬化症様病変と、他のモデル動物には見られない多彩な病態を呈する疾患モデル動物であるが、その原因遺伝子の詳細が明らかになっていなかった。本研究で同定した原因遺伝子の異常は、その病態（胸腺腫、筋萎縮）と関連しているという既報告例は無く、将来的に新しい切り口での治療への応用の可能性を秘めている点から学術的および社会的意義が深い研究成果である。また原因遺伝子の変異を導入した疾患モデル動物の作出、提供を通して研究成果をより広く社会に還元できる可能性がある。

Research Products

• [Journal Article] Resveratrol-induced transcriptional up-regulation of ASMase (SMPD1) of human leukemia and cancer cells. (2016)
  • Author(s): Mizutani N, Omori Y, Kawamoto Y, Sobue S, Ichihara M, Suzuki M, Kyogashima M, Nakamura M, Tamiya-Koizumi K, Nozawa Y, Murate T.
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 4 Pages: 851-856
  • DOI: 10.1016/j.bbrc.2016.01.134
  • Peer Reviewed
• [Journal Article] 分子状水素によるマウス肝臓における遺伝子発現変化の解析 (2016)
  • Author(s): 祖父江沙矢加、市原正智
  • Journal Title: 中部大学生命健康科学研究所紀要 Volume: 12 Pages: 38-41
  • NAID: 120006520501
  • Open Access
• [Journal Article] Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. (2015)
  • Author(s): Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K.
  • Journal Title: Med Gas Res Volume: 5 Issue: 1 Pages: 12-12
  • DOI: 10.1186/s13618-015-0035-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Development of effective method for preventing life environment factor-induced diseases using molecular hydrogen. (2015)
  • Author(s): Sobue S, Ichihara M.
  • Organizer: ICITE for SD-2015
  • Place of Presentation: Chubu University (Kasugai)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Molecular hydrogen is a novel antioxidant to reduce oxidative stress and attenuate disease progression through modification of cell signaling and gene expressions. (2015)
  • Author(s): Sobue S, Inoue C, Hori F, Ito M, Ohno K, Ichihara M.
  • Organizer: 15th International Conference on Oxidative Stress Reduction, Redox Homeostasis &Antioxidants
  • Place of Presentation: Paris (France)
  • Year and Date: 2015-06-24
  • Int'l Joint Research