Role of Pin1 on the pathgenesis of inflammatory bowel diseases

• Project/Area Number: 16K15431
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hiroshima University
• Principal Investigator: Asano Tomoichiro 広島大学, 医歯薬保健学研究科(医), 教授 (70242063)
• Co-Investigator(Kenkyū-buntansha): 中津 祐介 広島大学, 医歯薬保健学研究科(医), 講師 (20452584)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Pin1 / プロリン異性化酵素 / 炎症性腸疾患 / 潰瘍性大腸炎 / 炎症

Outline of Final Research Achievements

Pin1 is a unique peptidyl-propyl isomerase (PPIase). Pin1 specifically recognizes phosphorylated serine or threonine residues located immediately N-terminal to a proline and then isomerizes the peptide bound and catalyze isomerization of prolyl petide bonds from trans to cis.Inflammatory bowel disease (IBD) represents a group of inflammatory disorders in intestine. We found that Pin1 was markedly increased in the DSS-induced colitis mouse intestine. In addition, Pin1 KO mice showed high resistance to the DSS-induced colitis. We also performed the experiment to generate the novel Pin1 inhibitors. Oral administration of these inhibitors to mice inhibited the developm,ent of DSS-induced colitis. Taken together, it was demonstrated that Pin1 is involved in the development of inflammatory bowel diseases and that Pin1 inhibitors may be usable for the treatment with these disorders.

Research Products

• [Journal Article] A highly sensitive FRET biosensor for AMPK exhibits 1 heterogeneous AMPK responses among cells and organs. (2017)
  • Author(s): Konagaya, Y., Terai, K., Hirao, Y., Takakura, K., Imajo, M., Kamioka, Y., Sasaoka, N., Kakizuka, A., Sumiyama, K., Asano, T., and Matsuda, M.
  • Journal Title: Cell Rep. Volume: 21 Pages: 2628-2638
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal signals regulate obesity induced β-cell proliferation by FoxM1 dependent mechanism (2017)
  • Author(s): Yamamoto, J., Imai, J., Izumi, T., Takahashi, T., Kawana, Y., Takahashi, K., Kodama, S., Kaneko, K., Gao, J., Uno, K., Sawada, S., Asano, T., Kalinichenko, VV., Susaki, EA., Kanzaki, M., Ueda, HR., Ishigaki, Y., Yamada, T. and Katagiri, H.
  • Journal Title: Nat. Commun. Volume: 8 Pages: 1930-1930
  • Peer Reviewed / Open Access
• [Journal Article] Trk-fused gene (TFG) regulates pancreatic beta cell mass and insulin secretory activity (2017)
  • Author(s): Yamamotoya, T., Nakatsu, Y., Kushiyama, A., Matsunaga, Y., Ueda, K., Inoue, Y., Inoue, MK., Sakoda, H., Fujishiro, M., Ono, H., Kiyonari, H., Ishihara, H. and Asano, T.
  • Journal Title: Scientific Reports Volume: 7 Pages: 15035-15035
  • NAID: 120006796546
  • Peer Reviewed / Open Access
• [Journal Article] The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice. (2017)
  • Author(s): Nakatsu, Y., Kokubo, H., Bumdelger, B., Yoshizumi, M., Yamamotoya, T., Matsunaga, Y., Ueda, K., Inoue, Y., Inoue, MK., Fujishiro, M., Kushiyama, A., Ono, H., Sakoda, H. and Asano, T.
  • Journal Title: Int. J. Mol. Sci. Volume: 18 Pages: 1704-1704
  • Peer Reviewed / Open Access
• [Journal Article] The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion. (2017)
  • Author(s): Nakatsu, Y., Mori, K., Matsunaga, Y., Yamamotoya, T., Ueda, K., Inoue, Y., Mitsuzaki-Miyoshi, K., Sakoda, H., Fujishiro, M., Yamaguchi, S., Kushiyama, A., Ono, H., Ishihara, H., and Asano, T.
  • Journal Title: J. Biol. Chem. Volume: 292 Pages: 11886-11895
  • Peer Reviewed / Open Access
• [Journal Article] USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination (2017)
  • Author(s): Fukushima, T., Yoshihara, H., Furuta, H., Hakuno, F., Saeki, Y., Iemura, SI., Natsume, T., Nakatsu, Y., Kamata, H., Asano, T., Komada, M., Takahashi, SI.
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 484 Pages: 522-528
  • Peer Reviewed / Open Access
• [Journal Article] Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice. (2017)
  • Author(s): Yamamotoya, T., Nakatsu, Y., Matsunaga, Y., Fukushima, T., Yamazaki, H., Kaneko, S., Fujishiro, M., Kikuchi, T., Kushiyama, A., Tokunaga, F., Asano, T., Sakoda, H.
  • Journal Title: Int. J. Mol. Sci. Volume: １８ Pages: 326-326
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Resistin-like molecule beta in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice (2016)
  • Author(s): Okubo H., Kushiyama, A., Sakoda, H., Nakatsu, Y., Iizuka, M., Taki, N., Fujishiro, M., Fukushima, T., Kamata, H., Nagamachi, A., Inaba, T., Nishimura, F., Katagiri, H., Asahara, T., Yoshida, Y., Chonan, O., Encinas, J., and Asano, T.
  • Journal Title: Scientific Reports Volume: 6 Pages: 20157-20157
  • Peer Reviewed / Open Access
• [Journal Article] Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations. (2016)
  • Author(s): Nakatsu, Y., Matsunaga, Y., Yamamotoya, T., Ueda, K., Inoue, Y., Mori, K., Sakoda, H., Fujishiro, M., Ono, H., Kushiyama, A., and Asano, T.
  • Journal Title: Int. J. Mol. Sci. Volume: 17
  • Peer Reviewed / Open Access
• [Journal Article] IL-17A synergistically enhances TNFα-induced IL-6 and CCL20 production in 3T3-L1 adipocytes. (2016)
  • Author(s): Shinjo, T., Iwashita, M., Yamashita, A., Sano, T., Tsuruta, M., Matsunaga, H., Sanui, T., Asano, T., and Nishimura, F.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 477 Pages: 241-246
  • Peer Reviewed / Open Access
• [Journal Article] Role of uric acid metabolism-related inflammation in the pathogenesis of metabolic syndrome components such as atherosclerosis and non-alcoholic steatohepatitis (2016)
  • Author(s): Kushiyama, A., Nakatasu, Y., Matsunaga, Y., Yamamotoya, T., Mori, K., Ueda, K., Sakoda, H., Fujishiro, M., Ono, H., and Asano, T.
  • Journal Title: Mediators Inflamm. Volume: 2016 Pages: 8603164-8603164
  • Peer Reviewed / Open Access
• [Presentation] プロリン異性化酵素Pin1はATGL及びHSLに結合し、分解を促進する (2017)
  • Author(s): 井上 由貴、中津 祐介、山本屋 武、松永 泰花、迫田 秀之、藤城 緑、菊池 貴子、櫛山 暁史、浅野 知一郎
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] Trk-fused gene (TFG) の膵β細胞における役割の解明 (2017)
  • Author(s): 山本屋 武、中津 祐介、松永 泰花、井上 由貴、迫田 秀之、藤城 緑、山崎 広貴、菊池 貴子、櫛山 暁史、浅野 知一郎
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 組織特異的キサンチンオキシダーゼによるインスリン感受性と慢性炎症の制御 (2017)
  • Author(s): 櫛山 暁史、菊池 貴子、山崎 広貴、山本屋 武、中津 祐介、松永 泰花、藤城 緑、迫田 秀之、浅野 知一郎、岩本 安彦
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] エネルギー代謝調節機構がCCL19-CCR7経路を介した肥満およびインスリン抵抗性に及ぼす影響に関する検討 (2017)
  • Author(s): 佐野 朋美、岩下 未咲、新城 尊徳、山下 明子、浅野 知一郎、西村 英紀
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] プロリン異性化酵素Pin1は、PRDM16の分解を促進することで熱産生を抑制する (2017)
  • Author(s): 中津 祐介、山本屋 武、松永 泰花、井上 由貴、迫田 秀之、藤城 緑、櫛山 暁史、浅野 知一郎
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 性ホルモン結合グロブリン（SHBG）による脂肪量減少効果と抗炎症効果 (2016)
  • Author(s): 山崎 広貴、櫛山 暁史、迫田 秀之、藤城 緑、山本屋 武、菊池 貴子、金子 直、浅野 知一郎
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-05-20
• [Presentation] Pin1を介した熱産生調節機構及び肥満との関係解明 (2016)
  • Author(s): 松永 泰花、中津 祐介、櫛山 暁史、菊池 貴子、山本屋 武、鎌田 英明、浅野 知一郎
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-05-20
• [Presentation] Trk-fused gene（TFG）の膵β細胞における役割の解明 (2016)
  • Author(s): 山本屋 武 、中津 祐介、迫田 秀之、藤城 緑、山崎 広貴、菊池 貴子、浅野 知一郎、櫛山 暁史
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-05-20
• [Presentation] プロリン異性化酵素Pin1を介した膵β細胞調節機構の解明 (2016)
  • Author(s): 中津 祐介、森 馨一、松永 泰花、山本屋 武、藤城 緑、石原 寿光、浅野 知一郎
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-05-20
• [Presentation] 肝外キサンチンオキシダーゼのインスリン抵抗性への関与 (2016)
  • Author(s): 櫛山 暁史、菊池 貴子、山崎 広貴、迫田 秀之、藤城 緑、浅野 知一郎、岩本 安彦
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-05-20
• [Patent(Industrial Property Rights)] 新規化合物並びにそれを用いたPin1阻害剤、炎症性腸疾患治療剤及び大腸癌予防剤 (2017)
  • Inventor(s): 浅野 知一郎、中津 祐介、岡部 隆義、伊藤 久央
  • Industrial Property Rights Holder: 浅野 知一郎、中津 祐介、岡部 隆義、伊藤 久央
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Acquisition Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] 新規アミド系化合物、並びにそれを用いたPin1阻害剤、炎症性疾患の治療剤及び癌の治療剤 (2017)
  • Inventor(s): 浅野 知一郎、中津 祐介、岡部 隆義、伊藤 久央
  • Industrial Property Rights Holder: 浅野 知一郎、中津 祐介、岡部 隆義、伊藤 久央
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-152806
  • Filing Date: 2017
  • Acquisition Date: 2017
• [Patent(Industrial Property Rights)] 脂肪性肝疾患の治療剤及び肥満症の治療剤 (2017)
  • Inventor(s): 浅野 知一郎、中津 祐介、岡部 隆義、伊藤 久央
  • Industrial Property Rights Holder: 浅野 知一郎、中津 祐介、岡部 隆義、伊藤 久央
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-152807
  • Filing Date: 2017
  • Acquisition Date: 2017
• [Patent(Industrial Property Rights)] 新規アントラニル酸系化合物、並びにそれを用いたPin1阻害剤、炎症性疾患の治療剤及び癌の治療剤 (2017)
  • Inventor(s): 浅野 知一郎、中津 祐介、岡部 隆義、伊藤 久央
  • Industrial Property Rights Holder: 浅野 知一郎、中津 祐介、岡部 隆義、伊藤 久央
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-152808
  • Filing Date: 2017
  • Acquisition Date: 2017