Physiological and Pathological Function of Cellular Stress Responses

• Project/Area Number: 24390049
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Gunma University
• Principal Investigator: IWAWAKI Takao 群馬大学, 先端科学研究指導者育成ユニット, 講師 (50342754)
• Research Collaborator: OIKAWA Daisuke 群馬大学, 生体調節研究所, 助教 ; TAKAHASHI Yayoi 群馬大学, 先端科学研究指導者育成ユニット, 研究支援者 ; ASAI Chiaki 群馬大学, 先端科学研究指導者育成ユニット, 研究支援者 ; YOSHINO Mayuko 群馬大学, 先端科学研究指導者育成ユニット, 研究支援者
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2012: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 小胞体ストレス / 酸化ストレス / タンパク質品質管理 / 脂質代謝 / 炎症 / ガン / 炎症性腸疾患 / 癌 / ムチン / IRE1 / ATF4 / エリスロポエチン

Outline of Final Research Achievements

Since 2012, I have focused on visualization of cellular stress in vivo and functional analysis of IRE1 molecule and other ER stress responsive molecules. In the former research, we developed a transgenic mouse model for monitoring oxidative stress, and visualized oxidative stress with cerebral ischemia and maralia infection using the transgenic mice. In the latter research, we indicated that IRE1 and/or XBP1 contributes to function of dendritic cells, differentiation of B cells, lipid metabolism, acetaminophen metabolism, placental angiogenesis, suppression of intestinal tumorigenesis, and some functions of goblet cells and Paneth cells in guts.

Research Products

• [Journal Article] Correlation Between Attenuation of Protein Disulfide Isomerase Activity Through S-Mercuration and Neurotoxicity Induced by Methylmercury. (2015)
  • Author(s): Makino K, Okuda K, Sugino E, Nishiya T, Toyama T, Iwawaki T, Fujimura M, Kumagai Y, Uehara T.
  • Journal Title: Neurotox Res Volume: 27 Issue: 2 Pages: 99-105
  • DOI: 10.1007/s12640-014-9494-8
  • Peer Reviewed
• [Journal Article] Temporal activation of Nrf2 in the penumbra and Nrf2 activator-mediated neuroprotection in ischemia-reperfusionin jury (2014)
  • Author(s): Toshinori Takagi, Akira Kitashoji, Takao Iwawaki, Kazuhiro Tsuruma, Masamitsu Shimazawa, Shinichi Yoshimura, Toru Iwama, Hideaki Hara
  • Journal Title: Free Radic. Biol. Med. Volume: 72 Pages: 124-133
  • DOI: 10.1016/j.freeradbiomed.2014.04.009
  • Peer Reviewed / Open Access
• [Journal Article] Protection afforded by pre- or post-treatment with 4-phenylbutyrateagainst liver injury induced by acetaminophen overdose in mice (2014)
  • Author(s): Daisuke Shimizua, Yoichi Ishitsuka, Keishi Miyata, Yoshiro Tomishima, Yuki Kondo, Mitsuru Irikura, Takao Iwawaki, Yuichi Oike, Tetsumi Irie
  • Journal Title: Pharmacol. Res. Volume: 87 Pages: 26-41
  • DOI: 10.1016/j.phrs.2014.06.003
  • Peer Reviewed
• [Journal Article] Evaluating experimental cerebral malaria using oxidative stress indicator OKD48 mice. (2014)
  • Author(s): Imai T, Iwawaki T, Akai R, Suzue K, Hirai M, Taniguchi T, Okada H, Hisaeda H.
  • Journal Title: Int J Parasitol. Volume: 44 Issue: 10 Pages: 681-685
  • DOI: 10.1016/j.ijpara.2014.06.002
  • Peer Reviewed / Open Access
• [Journal Article] The co-chaperone and reductase ERdj5 facilitates rod opsin biogenesis and quality control (2014)
  • Author(s): Dimitra Athanasiou, Dalila Bevilacqua, Monica Aguila, Caroline McCulley, Naheed Kanuga, Takao Iwawaki, J. Paul Chapple, Michael E. Cheetham
  • Journal Title: Hum. Mol. Genet. Volume: 23 Issue: 24 Pages: 6594-6606
  • DOI: 10.1093/hmg/ddu385
  • Peer Reviewed
• [Journal Article] A role for regulated IRE-1 dependent decay in curtailing immunoglobulin secretion from plasma cells (2014)
  • Author(s): Sandrine Benhamron, Takao Iwawaki, Jae-Seon So, Ann-Hwee Lee, Boaz Tirosh
  • Journal Title: Eur. J. Immunol. Volume: 44 Issue: 3 Pages: 867-876
  • DOI: 10.1002/eji.201343953
  • Peer Reviewed
• [Journal Article] Inositol-requiring enzyme 1-α regulates CD8α+ dendritic cell function via regulated mRNA decay (2014)
  • Author(s): Fabiola Osorio, Simon Tavernier, Eik Hoffmann, Yvan Saeys, Liesbet Martens, Jessica Vetters, Iris Delrue, Riet De Rycke, Eef Parthoens, Philippe Poulliot, Takao Iwawaki, Sophie Janssens, Bart N. Lambrecht
  • Journal Title: Nat. Immunol. Volume: 15 Issue: 3 Pages: 248-257
  • DOI: 10.1038/ni.2808
  • Peer Reviewed
• [Journal Article] MTP inhibition induces ER stress and increases gene transcription via Ire1α/cJun to enhance plasma ALT/AST. (2013)
  • Author(s): Josekutty, J., Iqbal, J., Iwawaki, T., Kohno, K., and Hussain, M.
  • Journal Title: J. Biol. Chem. Volume: 288(20) Issue: 20 Pages: 14372-14383
  • DOI: 10.1074/jbc.m113.459602
  • Peer Reviewed
• [Journal Article] Positive contribution of IRE1α-XBP1 pathway to the expression of placental cathepsins (2013)
  • Author(s): Daisuke Oikawa, Takao Iwawaki
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 433 Issue: 4 Pages: 426-431
  • DOI: 10.1016/j.bbrc.2013.02.119
  • Peer Reviewed
• [Journal Article] CHOP is a critical regulator of acetaminophen-induced hepatotoxicity (2013)
  • Author(s): Dotan Uzi, Liran Barda, Viviana Scaiewicz, Maya Mills, Tobias Mueller, Agueda Gonzalez-Rodriguez, Angela M. Valverde, Takao Iwawaki, Yaakov Nahmias, Ramnik J. Xavier, Raymond T. Chung, Boaz Tirosh, Oren Shibolet
  • Journal Title: J. Hepatol. Volume: 59 Issue: 3 Pages: 495-503
  • DOI: 10.1016/j.jhep.2013.04.024
  • Peer Reviewed
• [Journal Article] ER stress transcription factor Xbp1 suppresses intestinal tumourigenesis and directs intestinal stem cells. (2013)
  • Author(s): Niederreiter, L., Fritz, T. M. J., Adolph, T.E., Krismer, A. M., Offner, F. A., Tschurtschenthaler, M., Flak, M. B., Hosomi, S., Tomczak, M. F., Kaneider, N. C., Sarcevic, E., Kempster, S. L., Raine, T., Esser, D., Rosenstiel, P., Kohno, K., Iwawaki, T., Tilg, H., Blumberg, R. S., and Kaser, A.
  • Journal Title: J. Exp. Med. Volume: 210(10) Issue: 10 Pages: 2041-2056
  • DOI: 10.1084/jem.20122341
  • Peer Reviewed
• [Journal Article] Comparative analysis of ER stress response into HIV protease inhibitors : Lopinavir but not Darunavir induces potent ER stress response via ROS/JNK pathway. (2013)
  • Author(s): Taura M, Kariya R, Kudo E, Goto H, Iwawaki T, Amano M, Suico MA, Kai H, Mitsuya H, Okada S.
  • Journal Title: Free Radical Biology and Medicine Volume: 65 Pages: 778-788
  • DOI: 10.1016/j.freeradbiomed.2013.08.161
  • Peer Reviewed
• [Journal Article] Paneth cells as a site of origin for intestinal inflammation (2013)
  • Author(s): Adolph,T.E.,Tomczak,M.F.,Niederreiter,L.,Ko,H.J.,Bock,J.,Martinez-Naves,E.,Glickman,J.N.,Tschurtschenthaler,M.,Hartwig,J.,Hosomi,S.,Flak,M.B.,Cusick,J.L.,Kohno,K.,Iwawaki,T.,Billmann-Born,S.,Raine,T.,Bharti,R.,Lucius,R.,Kweon,M.N.,Marciniak,S.J.,Choi,A.,Hagen,S.J.,Schreiber,S.,Rosenstiel,P.,Kaser,A.,Blumberg,RS.
  • Journal Title: Nature Volume: 503 Issue: 7475 Pages: 272-276
  • DOI: 10.1038/nature12599
  • Peer Reviewed
• [Journal Article] The role of the unfolded protein response in diabetes mellitus (2013)
  • Author(s): Takao Iwawaki, Daisuke Oikawa
  • Journal Title: Semin. Immunopathol. Volume: 35 Issue: 3 Pages: 333-350
  • DOI: 10.1007/s00281-013-0369-5
  • Peer Reviewed
• [Journal Article] 生きているマウスで酸化ストレスを見えるように (2013)
  • Author(s): 及川大輔、岩脇隆夫
  • Journal Title: 化学と生物 Volume: 51 Pages: 361-363
• [Journal Article] Endoplasmic reticulum stress signal impairs erythropoietin production:a role for ATF4. (2013)
  • Author(s): Chiang CK, Nangaku M, Tanaka T, IwawakiT, Inagi R.
  • Journal Title: Am J Physiol Cell Physiol. Volume: 304(4) Issue: 4 Pages: C342-C353
  • DOI: 10.1152/ajpcell.00153.2012
  • Peer Reviewed
• [Journal Article] Negative feedback by IRE1β optimizes mucin production in goblet cells. (2013)
  • Author(s): Tsuru, Akio
  • Journal Title: Proc Natl Acad Sci USA Volume: 110 Issue: 8 Pages: 2864-2869
  • DOI: 10.1073/pnas.1212484110
  • Peer Reviewed
• [Journal Article] 小胞体ストレスシグナルの感知・生体防御機構 (2013)
  • Author(s): 岩脇隆夫
  • Journal Title: 細胞 Volume: 45 Pages: 168-171
• [Journal Article] Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. (2012)
  • Author(s): Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, Narita T, Masaki A, Ito A, Ding J, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R, Iwawaki T, Imoto M, Iida S.
  • Journal Title: Blood Cancer J. Volume: 2 Issue: 7 Pages: e79-e79
  • DOI: 10.1038/bcj.2012.26
  • Peer Reviewed
• [Journal Article] Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice (2012)
  • Author(s): Jae-Seon So
  • Journal Title: Cell Metab. Volume: 16 Issue: 4 Pages: 487-499
  • DOI: 10.1016/j.cmet.2012.09.004
  • Peer Reviewed
• [Journal Article] Direct association of unfolded proteins with mammalian ER stress sensor, IRE1 beta. (2012)
  • Author(s): Oikawa D.
  • Journal Title: PLoS One. Volume: 7(12) Issue: 12 Pages: e51290-e51290
  • DOI: 10.1371/journal.pone.0051290
  • Peer Reviewed
• [Journal Article] 小胞体ストレスの可視化 (2012)
  • Author(s): 岩脇隆夫
  • Journal Title: 生体の科学 Volume: 65 Pages: 388-389
• [Presentation] 小胞体ストレス応答不全による糖尿病発症機構の解明 (2014)
  • Author(s): 斉藤美知子、土屋雄一、岩脇隆夫、森和俊、宮崎純一、河野憲二
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] インスリン生合成に必要な膵臓ベータ細胞におけるeIF2αキナーゼとホスファターゼのバランス機構 (2014)
  • Author(s): 岩脇 隆夫、赤井 良子、細田 章、徳田 美緒
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 群馬大学で名付けられた遺伝子、IRE1 (2014)
  • Author(s): 岩脇隆夫
  • Organizer: 第61回北関東医学会総会
  • Place of Presentation: 群馬大（群馬県前橋市）
  • Year and Date: 2014-09-25 – 2014-09-26
• [Presentation] 小胞体ストレスセンサーIRE1αによる細胞質スプライシングに必要なmRNAの構造及び配列の解析 (2014)
  • Author(s): 池端悠介、今川佑介、柳谷耕太、田丸良子、金谷重彦、岩脇隆夫、河野憲二
  • Organizer: 第66回日本細胞生物学会
  • Place of Presentation: 東大寺総合文化センター（奈良県奈良市）
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] インスリン産生細胞における小胞体ストレスセンサーIRE1alphaの生理的役割 (2014)
  • Author(s): 土屋雄一、斉藤美知子、岩脇隆夫、宮崎純一、河野憲二
  • Organizer: 第66回日本細胞生物学会
  • Place of Presentation: 東大寺総合文化センター（奈良県奈良市）
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] Unfolded protein response is differently activated by membrane lipid saturation and unfolded proteins in the endoplasmic reticulum (2014)
  • Author(s): Nozomu Kono, Yuto Kitai, Hiroyuki Ariyama, Daisuke Oikawa, Takao Iwawaki, Hiroyuki Arai
  • Organizer: FASEB SRC: Phospholipid Cell Signaling and Metabolism in Inflammation and Cancer
  • Place of Presentation: Niagara Falls (USA)
  • Year and Date: 2014-06-01 – 2014-06-06
• [Presentation] The role of ER stress responses in the control of blood glucose and the biosynthesis of insulin (2014)
  • Author(s): Ryoko Akai, Takao Iwawaki
  • Organizer: 7th APOCB Congress and ASCB Workshops
  • Place of Presentation: Biopolis（シンガポール）
• [Presentation] Positive contribution of IRE1α-XBP1 pathway to the expression of placental cathepsins (2014)
  • Author(s): Takao Iwawaki, Daisuke Oikawa
  • Organizer: 7th APOCB Congress and ASCB Workshops
  • Place of Presentation: Biopolis（シンガポール）
• [Presentation] 酸化ストレス可視化マウスを用いた脳マラリアの新しい評価法 (2014)
  • Author(s): 今井孝、岩脇隆夫、赤井良子、鈴江一友、平井誠、谷口委代、岡田紘子、久枝一
  • Organizer: 第83回日本寄生虫学会大会
  • Place of Presentation: 愛媛大学
• [Presentation] Fatty acid flux regulates IRE1α activity to control the NLRP3 inflammasome in myeloid cells (2013)
  • Author(s): Megan Robblee, Jess P. Abate, Alex Samocha, Takao Iwawaki, Suneil K. Koliwad
  • Organizer: The 2013 Meeting on Metabolic Signaling & Disease
  • Place of Presentation: Cold Spring Harbor（米国）
• [Presentation] 細胞ストレス可視化モデルマウスの開発とその性能 (2013)
  • Author(s): 岩脇隆夫
  • Organizer: 第86回日本生化学会バイオインダストリーセミナー
  • Place of Presentation: パシフィコ横浜
  • Invited
• [Presentation] 胎盤でのCathepsin遺伝子発現制御におけるIRE1αおよびXBP1の役割 (2013)
  • Author(s): 岩脇隆夫、及川大輔
  • Organizer: 第60回北関東医学会総会
  • Place of Presentation: 群馬大学
• [Presentation] 胎盤における小胞体ストレス応答分子の機能 (2012)
  • Author(s): 岩脇隆夫
  • Organizer: 第4回群馬分子医学研究会
  • Place of Presentation: 群馬大学
  • Year and Date: 2012-10-20
• [Presentation] High-sensitive in vivo detection of oxidative stress with OKD48 transgenic mice (2012)
  • Author(s): Daisuke Oikawa
  • Organizer: Joint Meeting of the 11th International Congress of Hyperthermic Oncology & the 29th Japanese Congress of Thermal Medicine
  • Place of Presentation: 京都
  • Year and Date: 2012-08-28
• [Presentation] High-sensitive in vivo detection of oxidative stress with OKD48 transgenic mice (2012)
  • Author(s): Daisuke Oikawa
  • Organizer: UK-Japan Research Symposium "Molecular Mechanisms of Stress Response in Disease"
  • Place of Presentation: つくば
• [Presentation] Negative feedback by IRE1β optimizes mucin production in goblet cells (2012)
  • Author(s): Akio Tsuru
  • Organizer: The 2010 Meeting on Molecular Chaperones & Stress Responses
  • Place of Presentation: Cold Spring Harbor
• [Presentation] High-sensitive in-vivo detection of oxidative stress with OKD48 mice (2012)
  • Author(s): Daisuke Oikawa
  • Organizer: Joint Meeting of the 45th Annual Meeting of the Japanese Society of Developmental Biologists & the 64th Annual Meeting of the Japanese Society for Cell Biology
  • Place of Presentation: 神戸
• [Presentation] Negative feedback by IRE1β optimizes mucin production in goblet cells (2012)
  • Author(s): Akio Tsuru
  • Organizer: Joint Meeting of the 45th Annual Meeting of the Japanese Society of Developmental Biologists & the 64th Annual Meeting of the Japanese Society for cell Biology
  • Place of Presentation: 神戸
• [Presentation] 酸化ストレス可視化モデルマウスの開発 (2012)
  • Author(s): 岩脇隆夫
  • Organizer: 第8回日本疲労学会総会・学術集会
  • Place of Presentation: 国立スポーツ科学センター
• [Presentation] OKD48マウスを用いた酸化ストレスの高感度生体検出 (2012)
  • Author(s): 及川大輔
  • Organizer: 第65回日本酸化ストレス学会学術集会
  • Place of Presentation: 徳島
• [Presentation] 酸化ストレス可視化モデルマウスの開発 (2012)
  • Author(s): 及川大輔
  • Organizer: 第59回北関東医学会総会
  • Place of Presentation: 群馬大学
• [Presentation] 低酸素ストレスレポーターの開発から見えてきた新たな課題 (2012)
  • Author(s): 原口瑞樹
  • Organizer: 第7回臨床ストレス応答学会
  • Place of Presentation: 東京女子医科大学
• [Presentation] 細胞ストレス可視化モデルマウスの開発とその性能 (2012)
  • Author(s): 岩脇隆夫
  • Organizer: 細胞センサーの分子機構・相互作用・ネットワーク研究会
  • Place of Presentation: 生理学研究所
• [Presentation] 活性酸素ダメージの生体イメージングに向けたレポーターシステムの構築～OKD48からの出発～ (2012)
  • Author(s): 及川大輔
  • Organizer: 第29回臨床フリーラジカル会議
  • Place of Presentation: 京都
• [Presentation] 小胞体ストレス応答不全による糖尿病発症機構の解明 (2012)
  • Author(s): 斉藤美知子
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] 細胞ストレス可視化モデルマウスの開発とその性能
  • Author(s): 岩脇隆夫
  • Organizer: 岡山大＆理研ジョイントシンポジウム「最先端計測技術のトレンド2013」
  • Place of Presentation: 岡山大学
  • Invited
• [Presentation] メチル水銀誘発性神経細胞死における小胞体ストレスの関与
  • Author(s): 奥田洸作、牧野堅人、外山喬士、西屋禎、岩脇隆夫、熊谷嘉人、上原孝
  • Organizer: 第123回日本薬理学会近畿部会
  • Place of Presentation: ウインクあいち
• [Presentation] 細胞ストレス可視化モデルマウスの開発とその性能
  • Author(s): 岩脇隆夫
  • Organizer: 第8回医工連携グループミーティング
  • Place of Presentation: 群馬大学
  • Invited
• [Presentation] 動物個体レベルでみる小胞体ストレス応答分子IRE1αの役割
  • Author(s): 岩脇隆夫
  • Organizer: 第122回東京大学生命環境科学セミナー
  • Place of Presentation: 東京大学
  • Invited
• [Presentation] 細胞ストレス可視化モデルマウスの開発とその性能
  • Author(s): 岩脇隆夫
  • Organizer: 第5回実験動物センター・テクニカルセミナー
  • Place of Presentation: 東京医科歯科大学
  • Invited
• [Patent(Industrial Property Rights)] 炎症レポーターシステム (2014)
  • Inventor(s): 岩脇隆夫、及川大輔、石川智夫、山村研一
  • Industrial Property Rights Holder: 群馬大学、熊本大学、株式会社トランスジェニック
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-07-31
  • Overseas