膵β細胞の再生増殖におけるヒトREGファミリー遺伝子の役割の解明

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25860220
• Research Institution: Nara Medical University
• Principal Investigator: 山内 晶世 奈良県立医科大学, 医学部, 助教 (70361110)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 再生増殖因子

Outline of Annual Research Achievements

膵β細胞の傷害時に発現する増殖因子として発見されたReg (Regenerating gene) 遺伝子は，ヒトでは５種類 (REG Iα, REG Iβ, REG III, HIP/PAP, REG IV) 存在するが，ヒトの膵β細胞の再生・増殖における発現については不明であった．本研究の目的は，傷害時のヒト膵β細胞におけるREG遺伝子の発現機構の解明である．
ヒト膵β細胞 (1.1B4細胞) において，IL-6とグルココルチコイド（デキサメサゾン，Dx）の同時刺激によって，REG Iα遺伝子の転写がJAK/STAT経路を介して著しく誘導されることを明らかにした．また，REG Iα遺伝子プロモーターの一塩基多型(SNPs)，-563G/Aと-10T/Cについて，マイナーアレルである -563A, -10Cで転写誘導が有意に減弱することを見出した．ルシフェラーゼ遺伝子を連結したREG Iα遺伝子プロモーターを染色体に組み込んだ1.1B4細胞を分離してIL-6+Dxで刺激した結果， -563A, -10Cをもつプロモーターを組み込んだ細胞は転写誘導が見られず，これらのSNPがREG Iα遺伝子の転写に関与することが示唆された．REG Iβ遺伝子もIL-6+Dxによって転写誘導されることを見出したため誘導機構を解析し，研究期間を延長してSNPsの影響も解析してデータを統合した．REG Iβ遺伝子転写誘導はREG Iα遺伝子と同様にJAK/STAT経路依存的であること，プロモーター内のSNPs (-231G/Aと-165A/C) についてはマイナーアレルで転写誘導が低下することを明らかにした．
以上の結果から，ヒトの膵β細胞の炎症時には，REG IαおよびREG Iβ遺伝子が発現誘導されて再生・増殖を促進することが示唆され，糖尿病予防・治療のターゲットになりうると考えられた．

Research Products

• [Journal Article] Significance of interleukin-6/STAT pathway for the gene expression of REG Iα, a new autoantigen in Sjogren’s syndrome patients, in salivary duct epithelial cells. (2016)
  • Author(s): Fujimura T, Fujimoto T, Itaya-Hironaka A, Miyaoka T, Yoshimoto K, Sakuramoto-Tsuchida S, Yamauchi A, Takeda M, Tsujinaka H, Tanaka Y, Takasawa S.
  • Journal Title: Clin. Rev. Allergy Immunol. Volume: - Pages: in press
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Iα, a new auto-antigen in Sjogren’s syndrome patients,in salivary duct epithelial cells. (2015)
  • Author(s): Fujimura T, Fujimoto T, Itaya-Hironaka A, Miyaoka T, Yoshimoto K, Yamauchi A, Sakuramoto-Tsuchida S, Kondo S, Takeda M, Tsujinaka H, Azuma M, Tanaka Y, Takasawa S.
  • Journal Title: Biochem. Biophys. Rep. Volume: 2 Pages: 69-74
  • DOI: 10.1016/j.bbrep.2015.05.006
  • Peer Reviewed / Open Access
• [Journal Article] Human retinal pigment epithelial cell proliferation by the combined stimulation of hydroquinone and advanced glycation end-products via up-regulation of VEGF gene. (2015)
  • Author(s): Tsujinaka H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Ota H, Takeda M, Fujimura T, Takasawa S, Ogata N.
  • Journal Title: Biochem. Biophys. Rep. Volume: 2 Pages: 123-131
  • DOI: 10.1016/j.bbrep.2015.05.005
  • Peer Reviewed / Open Access
• [Journal Article] Regenerating gene protein as a novel autoantigen in the pathogenesis of Sjogren's syndrome. (2015)
  • Author(s): Fujimoto T, Yoshimoto K, Fujimura T, Takeda M, Yamauchi A, Itaya-Hironaka A, Takasawa S.
  • Journal Title: Antibodies Volume: 4 Pages: 409-425
  • DOI: 10.3390/antib4040409
  • Peer Reviewed / Open Access
• [Presentation] Up-regulation of selenoprotein P, and HIP/PAP in hepatocytes by cyclic intermittent hypoxia. (2016)
  • Author(s): Ota H, Yamauchi M, Koyama N, Fujita Y, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Shobatake R, Tomoda K, Yoshikawa M, Takasawa S, Kimura H.
  • Organizer: American Thoracic Society International Conference 2016
  • Place of Presentation: San Francisco (U.S.A.)
  • Year and Date: 2016-05-13 – 2016-05-18
  • Int'l Joint Research
• [Presentation] Human retinal pigment epithelial cell proliferation by the combined addition of hydroquinone and advanced glycation end-products via up-regulation of VEGF gene. (2016)
  • Author(s): Tsujinaka H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Fujimura T, Shobatake R, Takasawa S, Ogata N.
  • Organizer: The Association for Research in Vision and Ophthalmology 2016
  • Place of Presentation: Seattle (U.S.A)
  • Year and Date: 2016-05-01 – 2016-05-05
  • Int'l Joint Research
• [Presentation] Cyclic intermittent hypoxia up-regulated mRNAs of selenoprotein P and HIP/PAP. (2016)
  • Author(s): Ota H, Yamauchi M, Tomoda K, Koyama N, Fujita Y, Itaya-Hironaka A, Sakuramoto-Tsuchida S, Yamauchi A, Takasawa S, Yoshikawa M, Kimura H.
  • Organizer: The 56th Annual Meeting of the Japanese Respiratory Society
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2016-04-08 – 2016-04-10
• [Presentation] Nucleotide sequence responsible for translational control of proinsulin synthesis in beta cells by glucose. (2015)
  • Author(s): Takasawa S, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Ota H, Fujimura T, Tsujinaka H, Shobatake R, Tsuchida C.
  • Organizer: World Diabetes Congress 2015
  • Place of Presentation: Vancouver (Canada)
  • Year and Date: 2015-11-30 – 2015-12-04
  • Int'l Joint Research
• [Presentation] Up-regulation of selenoprotein P, a diabetes-associated hepatokine, and HIP/PAP, a mitogenic factor for liver, in hepatocytes by intermittent hypoxia. (2015)
  • Author(s): Ota H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Fujimura T, Tsujinaka, H, Tomoda K, Yoshikawa M, Kimura H, Takasawa S.
  • Organizer: 51st European Association for the Study of Diabetes
  • Place of Presentation: Stockholm (Sweden)
  • Year and Date: 2015-09-14 – 2015-09-18
  • Int'l Joint Research
• [Presentation] Hydroquinone-damaged human retinal pigment epithelial cell proliferation by advanced glycation end-products via up-regulation of VEGF gene. (2015)
  • Author(s): Tsujinaka H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Ota H, Fujimura T, Shobatake R, Ogata N, Takasawa S.
  • Organizer: 51st European Association for the Study of Diabetes
  • Place of Presentation: Stockholm (Sweden)
  • Year and Date: 2015-09-14 – 2015-09-18
  • Int'l Joint Research
• [Presentation] Cyclic intermittent hypoxia induced insulin resistance via up-regulation of hepatokine gene. (2015)
  • Author(s): Ota H, Tamaki S, Yamauchi M, Tomoda K, Itaya-Hironaka A, Sakuramoto-Tsuchida S, Yamauchi A, Takasawa S, Yoshikawa M, Kimura H.
  • Organizer: The 55th Annual Meeting of the Japanese Respiratory Society
  • Place of Presentation: 東京国際フォーラム（東京都）
  • Year and Date: 2015-04-17 – 2015-04-19