Establishment of Pancreatic Beta-Cell Neogenesis from Pancreatic Duct Epithelial Cells by Genome Editing and Novel Diabetes Therapeutic Strategy

• Project/Area Number: 16K15432
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: International University of Health and Welfare (2017-2018); Kyushu University (2016)
• Principal Investigator: Ito Tetsuhide 国際医療福祉大学, 福岡看護学部, 教授 (50253448)
• Co-Investigator(Kenkyū-buntansha): 河邉 顕 九州大学, 大学病院, 助教 (10398068) ; 藤森 尚 九州大学, 大学病院, 助教 (60808137)
• Research Collaborator: MIKI Masami ; YASUNAGA Kohei
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ゲノム編集 / 膵管上皮細胞 / 膵β細胞新生 / 糖尿病治療 / 膵神経内分泌腫瘍 / 糖尿病 / 膵β細胞 / 分化誘導 / オートファジー / 膵臓 / fbw7 / β細胞

Outline of Final Research Achievements

We aimed to establish the induction of pancreatic B cell differentiation from pancreatic ductal epithelial cells in wild type mice using genome editing technology Crispr / Cas9 system and aim at treatment of diabetes by pancreatic B cell neoplasia. First, we used a pancreatic acinar cell line to knock out pancreatic amylase in Crispr / Cas9 to analyze autophagy, and demonstrated that pancreatic amylase loss may be involved in the onset of pancreatic cancer and diabetes progression through autophagy (BioMed Res Int, 2018). Furthermore, we performed gene expression analysis using RNA-Seq of pancreatic endocrine tumor cells and normal tissues, and proved that in tumors, synaptic transmission-related gene elevation and digestive enzyme-related enzymes decrease (Cancer Med, 2019). From now on, we will confirm the induction of differentiation of pancreatic B cells in terms of morphology and molecular biology.

Academic Significance and Societal Importance of the Research Achievements

糖尿病は多くの患者が罹患しているが、根治的かつ永続的な治療法は開発されていない。糖尿病では、血糖のコントロールを担っている膵B細胞におけるインスリン分泌低下が主要な要因である。膵B細胞のインスリン分泌を回復させる治療法の確立が必要である。本研究ではゲノム編集技術Crispr/Cas9システムという新しい技術を用いて、インスリンを産生する膵B細胞を他の細胞から分化誘導して糖尿病の治療に用いることが出来る可能性を見いだした。

Research Products

• [Journal Article] CLEC3A, MMP7, and LCN2 as Novel Markers for Predicting Recurrence in Resected G1 and G2 Pancreatic Neuroendocrine Tumors (2019)
  • Author(s): Miki M, Oono T, Fujimori N, Takaoka T, Kawabe K, Miyasaka Y, Ohtsuka T, Saito D, Nakamura M, Ohkawa Y, Oda N, Suyama M, Ito T, Ogawa Y.
  • Journal Title: Cancer Medicine Volume: in press Issue: 8 Pages: 3748-3760
  • DOI: 10.1002/cam4.2232
  • Peer Reviewed / Open Access
• [Journal Article] Using CRISPR/Cas9 to knock out amylase in acinar cells decreases pancreatitis-induced autophagy. (2018)
  • Author(s): Yasunaga K, Ito T, MIki M, Ueda K, Fujiyama T, Tachibana Y, Fujimori N, Kawabe K, Ogawa Y.
  • Journal Title: BioMed Research International Volume: Article ID 8719397, Pages: 1-8
  • DOI: 10.1155/2018/8719397
  • Peer Reviewed / Open Access
• [Journal Article] Using CRISPR/Cas9 to knock out amylase in acinar cells decreases pancreatitis-induced autophagy (2018)
  • Author(s): Yasunaga K, Ito T, MIki M, Ueda K, Fujiyama T, Tachibana Y, Fujimori N, Kawabe K, Ogawa Y.
  • Journal Title: BioMed Research International Volume: in press
  • Peer Reviewed
• [Journal Article] Rb Loss and KRAS Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study. (2017)
  • Author(s): Hijioka S, Hosoda W, Matsuo K, Ueno M, Furukawa M, Yoshitomi H, Kobayashi N, Ikeda M, Ito T, et al.
  • Journal Title: Clin Cancer Res Volume: 23 Issue: 16 Pages: 4625-4632
  • DOI: 10.1158/1078-0432.ccr-16-3135
  • Peer Reviewed
• [Journal Article] Utility of chromogranin B compared with chromogranin A as a biomarker in Japanese patients with pancreatic neuroendocrine tumors. (2017)
  • Author(s): Fujiyama T, Ito T, Ueda K, Tachibana Y, Yasunaga K, Miki M, Takaoka T, Lee L, Kawabe K, Ogawa Y.
  • Journal Title: J Dig Dis Volume: 47 Issue: 6 Pages: 520-528
  • DOI: 10.1093/jjco/hyx032
  • Peer Reviewed
• [Journal Article] Antifibrotic Effect of Saturated Fatty Acids via Endoplasmic Reticulum Stress Response in Rat Pancreatic Stellate Cells. (2017)
  • Author(s): Lee L, Ito T, Nakamura T, Jensen RT, Igarashi H, Takayanagi R.
  • Journal Title: Pancreas Volume: 46 Issue: 3 Pages: 385-394
  • DOI: 10.1097/mpa.0000000000000757
  • Peer Reviewed / Int'l Joint Research
• [Funded Workshop] 16th annual Eourope Neuroendocrine Tumor Society (ENETS) Conference (2019)