Transgenic mice for imaging of cellular stress associated with diseases and aging

• Project/Area Number: 18H02366
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: Kanazawa Medical University
• Principal Investigator: IWAWAKI Takao 金沢医科大学, 総合医学研究所, 教授 (50342754)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 細胞ストレス / 生体イメージング / 疾患モデル / 老化モデル

Outline of Final Research Achievements

It is important in life science research to capture life phenomena as they are alive, and bioimaging technology for that purpose has been rapidly advancing in recent years. By making good use of this technology, it is becoming useful for investigating the cause and developing treatments for certain diseases. There is a model mouse that introduces an optical reporter to support this technology, but there are still insufficient types to make a deep contribution in a wider field. In this study, we aimed for developing a new model mouse for bioimaging that visualizes three types of stress that are closely related to our health problems, and established two types of model mice within the period.

Academic Significance and Societal Importance of the Research Achievements

本研究で開発したモデルマウスは健康および生命維持に重要な生体恒常性に影響を与え、その破綻は重篤な疾患や老化促進に繋がる細胞ストレスを可視化するものである。このマウスを利用することで特定疾患の病態を詳細に理解でき、さらには予防法や治療法の開発に繋げることができる。その意味で本研究は基礎生命科学研究に留まらず、医学研究や薬学研究とも有機的に結びつくものとなっている。

Research Products

• [Int'l Joint Research] Baylor College of Medicine/University of California, San Diego/University of Washington, Seattle(米国)
• [Int'l Joint Research] McGill University(カナダ)
• [Int'l Joint Research] University College London(英国)
• [Int'l Joint Research] Linkoping University(スウェーデン)
• [Int'l Joint Research] University of Minnesota/Cornell University/University of Michigan(米国)
• [Int'l Joint Research] Northumbria University(英国)
• [Int'l Joint Research] Ajou University(韓国)
• [Int'l Joint Research] Linkoping University(スウェーデン)
• [Int'l Joint Research] Universidad de Chile(チリ)
• [Int'l Joint Research]
• [Int'l Joint Research] TAMU/Baylar College/NINDS/NIH(米国)
• [Int'l Joint Research] Martin Luther University/University Hospital Tubingen(ドイツ)
• [Int'l Joint Research] Institute of Zoology, CAS/National Center of Biomedical Analysis(中国)
• [Int'l Joint Research] VIB(ベルギー)
• [Int'l Joint Research] University of Chile(チリ)
• [Int'l Joint Research]
• [Journal Article] Apelin/APJ signaling suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model (2020)
  • Author(s): Yamazaki Sahori、Sekiguchi Akiko、Uchiyama Akihiko、Fujiwara Chisako、Inoue Yuta、Yokoyama Yoko、Ogino Sachiko、Torii Ryoko、Hosoi Mari、Akai Ryoko、Iwawaki Takao、Ishikawa Osamu、Motegi Sei-ichiro
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1349-1349
  • DOI: 10.1038/s41598-020-58452-2
  • Peer Reviewed / Open Access
• [Journal Article] Transgenic mouse model exhibiting weak red fluorescence before and strong green fluorescence after Cre/loxP-mediated recombination (2020)
  • Author(s): Akai Ryoko、Saito Michiko、Kohno Kenji、Iwawaki Takao
  • Journal Title: Experimental Animals Volume: 69 Issue: 3 Pages: 306-318
  • DOI: 10.1538/expanim.19-0085
  • NAID: 130007884759
  • Peer Reviewed / Open Access
• [Journal Article] Protective effect of dimethyl fumarate for the development of pressure ulcers after cutaneous ischemia‐reperfusion injury (2020)
  • Author(s): Inoue Yuta、Uchiyama Akihiko、Sekiguchi Akiko、Yamazaki Sahori、Fujiwara Chisako、Yokoyama Yoko、Ogino Sachiko、Torii Ryoko、Hosoi Mari、Akai Ryoko、Iwawaki Takao、Ishikawa Osamu、Motegi Sei‐ichiro
  • Journal Title: Wound Repair and Regeneration Volume: 28 Issue: 5 Pages: 600-608
  • DOI: 10.1111/wrr.12824
  • Peer Reviewed
• [Journal Article] AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity (2020)
  • Author(s): Aguila Monica、Bellingham James、Athanasiou Dimitra、Bevilacqua Dalila、Duran Yanai、Maswood Ryea、Parfitt David A、Iwawaki Takao、Spyrou Giannis、Smith Alexander J、Ali Robin R、Cheetham Michael E
  • Journal Title: Human Molecular Genetics Volume: 29 Issue: 8 Pages: 1310-1318
  • DOI: 10.1093/hmg/ddaa049
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IRE1α regulates macrophage polarization, PD-L1 expression, and tumor survival (2020)
  • Author(s): Batista Alyssa、Rodvold Jeffrey J.、Xian Su、Searles Stephen C.、Lew Alyssa、Iwawaki Takao、Almanza Gonzalo、Waller T. Cameron、Lin Jonathan、Jepsen Kristen、Carter Hannah、Zanetti Maurizio
  • Journal Title: PLOS Biology Volume: 18 Issue: 6 Pages: e3000687-e3000687
  • DOI: 10.1371/journal.pbio.3000687
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions (2020)
  • Author(s): Xu Longyong、Iwawaki Takao、Chen Xi et al
  • Journal Title: Nature Cell Biology Volume: 22 Issue: 10 Pages: 1162-1169
  • DOI: 10.1038/s41556-020-00581-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of IRE1α in podocyte proteostasis and mitochondrial health (2020)
  • Author(s): Navarro-Betancourt Jos? R.、Papillon Joan、Guillemette Julie、Iwawaki Takao、Chung Chen-Fang、Cybulsky Andrey V.
  • Journal Title: Cell Death Discovery Volume: 6 Issue: 1 Pages: 128-128
  • DOI: 10.1038/s41420-020-00361-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IRE1α Promotes Zika Virus Infection via XBP1 (2020)
  • Author(s): Kolpikova Elena P.、Tronco Ana R.、Den Hartigh Andreas B.、Jackson Konner J.、Iwawaki Takao、Fink Susan L.
  • Journal Title: Viruses Volume: 12 Issue: 3 Pages: 278-278
  • DOI: 10.3390/v12030278
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication (2019)
  • Author(s): Antoniou AN, Lenart I, Kriston-Vizi J, Iwawaki T, Turmaine M, McHugh K, Ali S, Blake N, Bowness P, Bajaj-Elliott M, Gould K, Nesbeth D, Powis SJ
  • Journal Title: Ann Rheum Dis Volume: 78 Issue: 1 Pages: 74-82
  • DOI: 10.1136/annrheumdis-2018-213532
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IRE1α Activation in Bone Marrow-Derived Dendritic Cells Modulates Innate Recognition of Melanoma Cells and Favors CD8+ T Cell Priming (2019)
  • Author(s): Medel B, Costoya C, Fernandez D, Pereda C, Lladser A, Sauma D, Pacheco R, Iwawaki T, Salazar-Onfray F, Osorio F
  • Journal Title: Front Immunol Volume: 9 Pages: 3050-3050
  • DOI: 10.3389/fimmu.2018.03050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells (2019)
  • Author(s): Liu L, Zhao M, Jin X, Ney G, Yang KB, Peng F, Cao J, Iwawaki T, Del Valle J, Chen X, Li Q
  • Journal Title: Nat Cell Biol Volume: 21 Issue: 3 Pages: 328-337
  • DOI: 10.1038/s41556-019-0285-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ablation of the Chaperone Protein ERdj5 Results in a Sjogren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients (2019)
  • Author(s): Apostolou E, Moustardas P, Iwawaki T, Tzioufas AG, Spyrou G
  • Journal Title: Front Immunol Volume: 10 Pages: 506-506
  • DOI: 10.3389/fimmu.2019.00506
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ERdj5 in Innate Immune Cells Is a Crucial Factor for the Mucosal Adjuvanticity of Cholera Toxin (2019)
  • Author(s): Kim MS, Yi EJ, Kim YI, Kim SH, Jung YS, Kim SR, Iwawaki T, Ko HJ, Chang SY
  • Journal Title: Front Immunol Volume: 10 Pages: 1249-1249
  • DOI: 10.3389/fimmu.2019.01249
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1 (2019)
  • Author(s): Suzuki Takafumi、Muramatsu Aki、Saito Ryota、Iso Tatsuro、Shibata Takahiro、Kuwata Keiko、Kawaguchi Shin-ichi、Iwawaki Takao、Adachi Saki、Suda Hiromi、Morita Masanobu、Uchida Koji、Baird Liam、Yamamoto Masayuki
  • Journal Title: Cell Reports Volume: 28 Issue: 3 Pages: 746-758
  • DOI: 10.1016/j.celrep.2019.06.047
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain (2019)
  • Author(s): Chopra S, Giovanelli P, Alvarado-Vazquez PA, Alonso S, Song M, Sandoval TA, Chae CS, Tan C, Fonseca MM, Gutierrez S, Jimenez L, Subbaramaiah K, Iwawaki T, Kingsley PJ, Marnett LJ, Kossenkov AV, Crespo MS, Dannenberg AJ, Glimcher LH, Romero-Sandoval EA, Cubillos-Ruiz JR
  • Journal Title: Science Volume: 365 Issue: 6450
  • DOI: 10.1126/science.aau6499
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Zinc deficiency exacerbates pressure ulcers by increasing oxidative stress and ATP in the skin (2019)
  • Author(s): Nakamura H, Sekiguchi A, Ogawa Y, Kawamura T, Akai R, Iwawaki T, Makiguchi T, Yokoo S, Ishikawa O, Motegi SI
  • Journal Title: J Dermatol Sci Volume: 95 Issue: 2 Pages: 62-69
  • DOI: 10.1016/j.jdermsci.2019.07.004
  • Peer Reviewed
• [Journal Article] MITOL prevemts ER stress-induced apoptosis by IRE1 ubiquitylation at mitochondrial-ER contact sites. (2019)
  • Author(s): Takeda, K., Nagashima, S., Shiiba, I., Uda, A., Tokuyama, T., Ito, N., Fukuda, T., Matsushita, N., Ishido, S., Iwawaki, T., Uehara, T., Inatome, R., and Yanagi, S.
  • Journal Title: EMBO J. Volume: 38 Issue: 15
  • DOI: 10.15252/embj.2018100999
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effect of kaempferol on skin fibrosis in systemic sclerosis by the suppression of oxidative stress (2019)
  • Author(s): Sekiguchi A, Motegi SI, Fujiwara C, Yamazaki S, Inoue Y, Uchiyama A, Akai R, Iwawaki T, Ishikawa O
  • Journal Title: J Dermatol Sci Volume: 96 Issue: 1 Pages: 8-17
  • DOI: 10.1016/j.jdermsci.2019.08.004
  • Peer Reviewed
• [Journal Article] Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD (2019)
  • Author(s): Koehn BH, Saha A, McDonald-Hyman C, Loschi M, Thangavelu G, Ma L, Zaiken M, Dysthe J, Krepps W, Panthera J, Hippen K, Jameson SC, Miller JS, Cooper MA, Farady CJ, Iwawaki T, Ting JP, Serody JS, Murphy WJ, Hill GR, Murray PJ, Bronte V, Munn DH, Zeiser R, Blazar BR
  • Journal Title: Blood Volume: 134 Issue: 19 Pages: 1670-1682
  • DOI: 10.1182/blood.2019001950
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Stabilization of cytokine mRNAs in iNKT cells requires the serine-threonine?kinase IRE1alpha (2018)
  • Author(s): Govindarajan S, Gaublomme D, Van der Cruyssen R, Verheugen E, Van Gassen S, Saeys Y, Tavernier S, Iwawaki T, Bloch Y, Savvides SN, Lambrecht BN, Janssens S, Elewaut D, Drennan MB
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 5340-5340
  • DOI: 10.1038/s41467-018-07758-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 小胞体ストレスの生体イメージング (2018)
  • Author(s): 岩脇隆夫, 赤井良子
  • Journal Title: THE BONE Volume: 32 Pages: 171-177
• [Journal Article] IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A (2018)
  • Author(s): Urra H, Henriquez DR, Canovas J, Villarroel-Campos D, Carreras-Sureda A, Pulgar E, Molina E, Hazari YM, Limia CM, Alvarez-Rojas S, Figueroa R, Vidal RL, Rodriguez DA, Rivera CA, Court FA, Couve A, Qi L, Chevet E, Akai R, Iwawaki T, Concha ML, Glavic A, Gonzalez-Billault C, Hetz C
  • Journal Title: Nature Cell Biology Volume: 20 Issue: 8 Pages: 942-953
  • DOI: 10.1038/s41556-018-0141-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] タンパク質恒常性と糖代謝異常に関わる小胞体ストレス応答の役割 (2018)
  • Author(s): 岩脇隆夫
  • Journal Title: 金沢医科大学雑誌 Volume: 43 Pages: 15-22
  • Peer Reviewed
• [Journal Article] Botulinum toxin B suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model: Possible regulation of oxidative and endoplasmic reticulum stress (2018)
  • Author(s): Sekiguchi A, Motegi SI, Uchiyama A, Uehara A, Fujiwara C, Yamazaki S, Perera B, Nakamura H, Ogino S, Yokoyama Y, Akai R, Iwawaki T, Ishikawa O
  • Journal Title: Journal of Dermatological Science Volume: 90 Issue: 2 Pages: 144-153
  • DOI: 10.1016/j.jdermsci.2018.01.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Activation of Host IRE1α-Dependent Signaling Axis Contributes the Intracellular Parasitism of Brucella melitensis (2018)
  • Author(s): Pandey A, Lin F, Cabello AL, da Costa LF, Feng X, Feng HQ, Zhang MZ, Iwawaki T, Rice-Ficht A, Ficht TA, de Figueiredo P, Qin QM
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 8 Pages: 103-103
  • DOI: 10.3389/fcimb.2018.00103
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells (2018)
  • Author(s): Yuichi Tsuchiya, Michiko Saito, Hiroshi Kadokura, Jun-ichi Miyazaki, Fumi Tashiro, Yusuke Imagawa, Takao Iwawaki, Kenji Kohno
  • Journal Title: The Journal of Cell Biology Volume: 217 Issue: 4 Pages: 1287-1301
  • DOI: 10.1083/jcb.201707143
  • Peer Reviewed / Open Access
• [Journal Article] ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response (2018)
  • Author(s): Chapple RH, Hu T, Tseng YJ, Liu L, Kitano A, Luu V, Hoegenauer KA, Iwawaki T, Li Q, Nakada D
  • Journal Title: eLife Volume: 7
  • DOI: 10.7554/elife.31159
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ストレス可視化モデルマウスの開発と疲労研究への応用 (2020)
  • Author(s): 岩脇隆夫、赤井良子
  • Organizer: 第16回日本疲労学会総会・学術集会
• [Presentation] IRE1α Is Essential for Podocyte Proteostasis and Mitochondrial Health (2020)
  • Author(s): Jose R. Navarro-Betancourt, Joan Papillon, Julie Guillemette, Takao Iwawaki, Andrey V. Cybulsky
  • Organizer: KIDNEY WEEK 2020
  • Int'l Joint Research
• [Presentation] Role of IRE1α in Podocyte Proteostasis (2019)
  • Author(s): Jose R Navarro-Betancourt, Joan Papillon, Julie Guillemette, Takao Iwawaki, Andrey V Cybulsky
  • Organizer: KIDNEY WEEK 2019
• [Presentation] 小胞体ストレス応答分子により制御される過食行動の分子メカニズム (2019)
  • Author(s): 岩脇隆夫、赤井良子
  • Organizer: 第14回臨床ストレス応答学会大会
• [Presentation] Comparison between endoscopic and histopathological findings in patients with ulcerative colitis (2019)
  • Author(s): Tetsuo Nakayama, Shiko Kuribayashi, Junko Hirato, Takao Iwawaki, Ko Nakata, Hirohito Tanaka, Taku Tomizawa, Hiroko Hosaka, Yasuyuki Shimoyama, Osamu Kawamura, Motoyasu Kusano, Toshio Uraoka
  • Organizer: Digestive Disease Week 2019
• [Presentation] 睡眠不足モデルマウスにおける細胞ストレス応答と炎症反応の生体イメージング (2019)
  • Author(s): 赤井良子、岩脇隆夫
  • Organizer: 第66回日本実験動物学会
• [Presentation] ATF4の翻訳活性化機構を利用した統合ストレス可視化モデルマウスの開発 (2018)
  • Author(s): 赤井良子, 岩脇隆夫
  • Organizer: 住商ファーマインターナショナル株式会社in vivoイメージングフォーラム2018
• [Presentation] 細菌によって利用される宿主細胞の生体防御反応～小胞体ストレス応答～ (2018)
  • Author(s): 岩脇隆夫
  • Organizer: 第55回日本細菌学会中部支部学術集会
  • Invited
• [Presentation] 細胞ストレスおよび炎症可視化モデルマウスの開発とその性能 (2018)
  • Author(s): 岩脇隆夫
  • Organizer: 第342回熊本大学・発生研セミナー
  • Invited
• [Presentation] 細胞ストレスおよび炎症可視化モデルマウスの開発とその性能 (2018)
  • Author(s): 岩脇隆夫
  • Organizer: 第16回京都薬科大学・実験動物セミナー
  • Invited
• [Presentation] 『見えない』を『見える』にするマウス (2018)
  • Author(s): 岩脇隆夫
  • Organizer: 第20回KMU研究推進セミナー
• [Presentation] ATF4の翻訳活性化機構を利用した統合ストレス可視化モデルマウスの開発と疲労研究への応用 (2018)
  • Author(s): 岩脇隆夫, 赤井良子
  • Organizer: 第14回日本疲労学会総会・学術集会
• [Presentation] ATF4の翻訳活性化機構を利用した統合ストレス可視化モデルマウスの開発 (2018)
  • Author(s): 赤井良子, 岩脇隆夫
  • Organizer: 第65回日本実験動物学会
• [Remarks]
  • URL: http://mri-cell-medicine.kanazawa-med.labos.ac/one/
• [Remarks]
  • URL: http://www.kanazawa-med.ac.jp/~souiken/ls/dcm/