Clarify the mechanisms in development of alcohol dependence by functional RNA analysis

• Project/Area Number: 16K08913
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Sapporo Medical University
• Principal Investigator: Mizuo Keisuke 札幌医科大学, 医学部, 講師 (90459735)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); 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)
• Keywords: アルコール / RNA / microRNA / マイクロアレイ / toll-like receptor / 依存・再燃 / 機能性RNA

Outline of Final Research Achievements

Alcoholism is a complex disorder resulting from multiple interaction between genetic, epigenetic and environmental factors. Alcohol dependence, a major symptom in the alcoholism, has spread worldwide, and the number of the patient is over a million in Japan. In the present study, we investigated the expression of miRNAs in mouse ethanol dependence model. The mice chronically treated with ethanol revealed severe withdrawal signs after discontinuation of ethanol. Total RNA was extracted from mouse limbic forebrain (containing nucleus accumbens). Comprehensive analysis of miRNA expression in ethanol dependence was performed by miRNA array. The miRNA array analysis showed 47 upregulated miRNAs in the ethanol dependence. These findings suggest that the upregulation of miRNAs may associate with the development of ethanol dependence.

Academic Significance and Societal Importance of the Research Achievements

本研究ではアルコール依存時において特異的に変化するマイクロRNAを見出した。この結果はアルコール依存の診断においてマイクロRNAが有用である可能性を示している。また、マイクロRNAのターゲット分子としてTLR4がアルコール依存形成に深く関わっていることを見出したことは、未だ有用な治療薬が存在しないアルコール依存症の治療薬の開発に寄与できる可能性を示すことができた。

Research Products

• [Presentation] Implications of innate immune systems in the development of ethanol dependence by changes in the expression of microRNAs in the brain (2018)
  • Author(s): Keisuke Mizuo, Tomoka Yamaguchi, Satoshi Watanabe
  • Organizer: 24th Congress of the International Academy of Legal Medicine
  • Int'l Joint Research
• [Presentation] Implications of toll-like receptor signaling in the development of ethanol dependence in mice brain (2018)
  • Author(s): Keisuke Mizuo, Satoshi Watanabe
  • Organizer: Neuroscience 2018
  • Int'l Joint Research
• [Presentation] アルコール依存時および離脱時における腹側被蓋野でのmicroRNA発現変動 (2017)
  • Author(s): 水尾圭祐、村上里奈、岡崎俊一郎、渡邊 智
  • Organizer: 第101次日本法医学会学術全国集会
• [Presentation] アルコール依存時の脳における免疫関連microRNAの発現変動 (2017)
  • Author(s): 水尾圭祐、渡邊 智
  • Organizer: 第18回日本法医学会学術北日本地方集会（法医学談話会第104回例会）
• [Presentation] Comparison of microRNAs expression between ethanol and methamphetamine dependence (2017)
  • Author(s): Keisuke Mizuo, Satoshi Watanabe
  • Organizer: Neuroscience 2017
  • Int'l Joint Research
• [Presentation] Chronic ethanol consumption and withdrawal affect the expression of microRNAs in mouse brain (2016)
  • Author(s): Keisuke Mizuo, Rina Murakami, Shunichiro Okazaki, Satoshi Watanabe
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research