Construction of transgenic mice that can image pathological states for elucidating disease onset mechanism

• Project/Area Number: 25250012
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: Kizaka-Kondoh Shinae 東京工業大学, 生命理工学研究科, 教授 (40314182)
• Co-Investigator(Kenkyū-buntansha): Mizusihima Tomoko 公益財団法人実験動物中央研究所, 試験事業部, 研究員 (90311240) ; Kondoh Gen 京都大学, 再生医科学研究所, 教授 (40243258)
• Project Period (FY): 2013-10-21 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥43,160,000 (Direct Cost: ¥33,200,000、Indirect Cost: ¥9,960,000); Fiscal Year 2015: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2014: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2013: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
• Keywords: 病態イメージング / トランスジェニックマウス / 低酸素誘導転写因子 / 発がん / 生体発光イメージング / HIF

Outline of Final Research Achievements

Genetically modified mice with a reporter gene for monitoring a specific factor's activity are useful tools to analyze the progression of a disease and to develop new drugs and treatment strategies for the disease. Hypoxia-inducible factor (HIF) is a master transcriptional regulator for many biological aspects and thus is related to serious diseases such as cancer. In this study, we newly developed transgenic (Tg) mice that emit bioluminescent and fluorescent signals in response to HIF activation in tissues under pathological condition. We especially aimed to construct Tg mice that can detect carcinogenicity of a reagent within several months by combining with rasH2 mice that are currently used for detecting carcinogenicity within 26 weeks. Such Tg mice will be able to accelerate new drug development by further shortening the detection time of carcinogenicity.

Research Products

• [Journal Article] High resolution imaging of intracellular oxygen concentration by phosphorescence lifetime (2015)
  • Author(s): Kurokawa H, Ito H, Inoue M, Tabata K, Sato Y, Yamagata K, Kizaka-Kondoh S, Kadonosono T, Yano S, Kamachi T.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 10657-10657
  • DOI: 10.1038/srep10657
  • Peer Reviewed / Open Access
• [Journal Article] The effect of triamcinolone acetonide on laser-induced choroidal neovascularization in mice using a hypoxia visualization bio-imaging probe. (2015)
  • Author(s): Takata S, Masuda T, Nakamura S, Kuchimaru T, Tsuruma K, Shimazawa M, Nagasawa H, Kizaka-Kondoh S, Hara H.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 9898-9898
  • DOI: 10.1038/srep09898
  • Peer Reviewed / Open Access
• [Journal Article] Cell penetrating peptides improve tumor delivery of cargos through Neuropilin-1-dependent extravasation. (2015)
  • Author(s): Kadonosono T, Yamano A, Goto T, Tsubaki T, Niibori M, Kuchimaru T, Kizaka-Kondoh S.
  • Journal Title: J. Control. Release Volume: 201 Pages: 14-21
  • DOI: 10.1016/j.jconrel.2015.01.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] nnate Response to Human Cancer Cells with or without IL-2 Receptor Common γ-Chain Function in NOD Background Mice Lacking Adaptive Immunity. (2015)
  • Author(s): Nishime C, Kawai K, Yamamoto T, Katano I, Monnai M, Goda N, Mizushima T, Suemizu H, Nakamura M, Murata M, Suematsu M, Wakui M.
  • Journal Title: J Immunol Volume: 195 Issue: 4 Pages: 1883-1890
  • DOI: 10.4049/jimmunol.1402103
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of Helios reporter mice and an evaluation of the suppressive capacity of Helios+ regulatory T cells in vitro (2015)
  • Author(s): Sugita K., Hanakawa S., Honda T., Kondoh G., Miyachi Y., Kabashima K., Nomura T.
  • Journal Title: Experimental Dermatology Volume: Ahead of print Issue: 7 Pages: 554-556
  • DOI: 10.1111/exd.12711
  • NAID: 120005674664
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9-based Rett syndrome model mouse. (2015)
  • Author(s): Tsuchiya Y., Minami Y., Umemura Y., Watanabe H., Ono D., Nakamura W., Takahashi T., Honma S., Kondoh G., Matsuishi T. & Yagita K.
  • Journal Title: Genes to Cells Volume: 20 Issue: 12 Pages: 992-1005
  • DOI: 10.1111/gtc.12305
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] がん間質における低酸素応答が悪性化を駆動する (2015)
  • Author(s): 近藤科江、口丸高弘、門之園哲哉
  • Journal Title: 実験医学 Volume: 33 Pages: 758-764
• [Journal Article] A fluorescent protein scaffold for presenting structurally constrained peptides provides an effective screening system to identify high affinity target-binding peptides. (2014)
  • Author(s): Kadonosono T, Yabe E, Furuta T, Yamano A, Tsubaki T, Sekine T, Kuchimaru T, Sakurai M, Kizaka-Kondoh S.
  • Journal Title: PLoS One Volume: 9 Issue: 8 Pages: e103397-e103397
  • DOI: 10.1371/journal.pone.0103397
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bone resorption facilitates osteoblastic bone metastatic colonization by cooperation of insulin-like growth factor and hypoxia. (2014)
  • Author(s): Kuchimaru T, Hoshino T, Aikawa T, Yasuda H, Kobayashi T, Kadonosono T, Kizaka-Kondoh S.
  • Journal Title: Cancer Science Volume: 105 Issue: 5 Pages: 553-559
  • DOI: 10.1111/cas.12391
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development of a novel interferon-α2b gene construct with a repetitive hypoxia-inducible factor binding site and its suppressive effects on human renal cell carcinoma cell lines in vitro. (2014)
  • Author(s): Fukui N, Kageyama Y, Higashi Y, Kihara K, Kizaka-Kondoh S, Hiraoka M, Shinojima T, Suzuki K, Oya M.
  • Journal Title: Int J Clin Oncol. Volume: 19 Issue: 3 Pages: 497-504
  • DOI: 10.1007/s10147-013-0568-z
  • Peer Reviewed / Open Access
• [Journal Article] Female-specific rectal carcinogenesis in cyclin D1b transgenic mice. (2014)
  • Author(s): Tambe, Y., Kim, C. J., Munkaisho, K., Sugihara, H., Isono, T., Sonoda, H., Shimizu, T., Kondoh, G., Inoue, H.
  • Journal Title: Carcinogenesis Volume: 35 Issue: 1 Pages: 227-236
  • DOI: 10.1093/carcin/bgt293
  • Peer Reviewed
• [Journal Article] Lipocalin2 binds to membrane phosphatidylethanolamine to induce lipid raft movement in a PKA-dependent manner and modulates sperm maturation. (2014)
  • Author(s): Watanabe, H., T. Takeo, H. Tojo, K. Sakoh, T. Berger, N. Nakagata, T. W. Mak, and G. Kondoh
  • Journal Title: Development Volume: 141 Issue: 10 Pages: 2157-2164
  • DOI: 10.1242/dev.105148
  • Peer Reviewed
• [Journal Article] 腫瘍内低酸素環境を標的とした癌治療戦略 (2014)
  • Author(s): 近藤科江
  • Journal Title: Surgery Frontier Volume: 21 Pages: 47-52
• [Journal Article] Development of an Oxygen-Sensitive Degradable Peptide Probe for the Imaging of Hypoxia-Inducible Factor-1-Active Regions in Tumors. (2013)
  • Author(s): Ueda M, Ogawa K, Miyano A, Ono M, Kizaka-Kondoh S, Saji H.
  • Journal Title: Mol Imaging Biol. Volume: 15 Issue: 6 Pages: 713-721
  • DOI: 10.1007/s11307-013-0647-6
  • Peer Reviewed
• [Journal Article] Importance of the physicochemical properties of fluorescence dyes for obtaining target-specific in vivo images by membrane-permeable macromolecular imaging probes (2013)
  • Author(s): Kuchimaru T, Kadonosono T, Corona C, Dwight SJ, McDougall M, Takahashi S, Mori T, Okahata Y, Kizaka-Kondoh S
  • Journal Title: J Pharmacol Tech Drug Res Volume: 2:3 Issue: 1 Pages: 1-7
  • DOI: 10.7243/2050-120x-2-2
  • Peer Reviewed / Open Access
• [Journal Article] Radiosynthesis and initial evaluation of 18F labeled nanocarrier composed of poly(L-lactic acid)-block-poly(sarcosine) amphiphilic polydepsipeptide. (2013)
  • Author(s): F.Yamamoto, R.Yamahara, A.Makino, K.Kurihara, H.Tsukada, E.Hara, I.Hara, S.Kizaka-Kondoh, Y.Ohkubo, E.Ozeki, S.Kimura
  • Journal Title: Nucl. Med. Biol. Volume: 40 Issue: 3 Pages: 387-394
  • DOI: 10.1016/j.nucmedbio.2012.12.008
  • Peer Reviewed
• [Journal Article] The protective role of the transmembrane thioredoxin-related protein TMX in inflammatory liver injury (2013)
  • Author(s): Matsuo Y, Irie K, Kiyonari H, Okuyama H, Nakamura H, Son A, Lopez-Ramos DA, Tian H, Oka S, Okawa K, Kizaka-Kondoh S, Masut ani H, Yodoi J
  • Journal Title: Antioxid Redox Signal Volume: 18(11) Issue: 11 Pages: 1263-1272
  • DOI: 10.1089/ars.2011.4430
  • Peer Reviewed / Open Access
• [Journal Article] Expression of TEX101, regulated by ACE, is essential for the production of fertile mouse sperm. (2013)
  • Author(s): Fujihara, Y., K. Tokuhiro, Y. Muro, G. Kondoh, Y. Araki, M. Ikawa, M. Okabe.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Pages: 8111-8116
  • Peer Reviewed
• [Journal Article] An in vitro ES cell-based clock recapitulation assay model identifies CK2a as an endogenous clock regulator (2013)
  • Author(s): Umemura Y, Yoshida J, Wada M, Tsuchiya Y, Minami Y, Watanabe H, Kondoh G, Takeda J, Inokawa H, Horie K, Yagita K.
  • Journal Title: PLoS One Volume: 8 Issue: 6 Pages: e67241-e67241
  • DOI: 10.1371/journal.pone.0067241
  • Peer Reviewed / Open Access
• [Journal Article] 機能イメージングによる病的低酸素の検出 (2013)
  • Author(s): 近藤科江
  • Journal Title: 医学のあゆみ Volume: 244 Pages: 334-335
• [Presentation] Short-term Carcinogenicity Study on C57BL/6J-Tyr[X]-rasH2 (Albino-rasH2) Mice, a Novel Strain for in vivo Tumor Imaging (2016)
  • Author(s): T. Mizushima, K. Urano, R. Inoue, M. Yasuda, M. Goto, T. Kagawa, T. Kadonosono, T. Kuchimaru and S. Kizaka-Kondoh.
  • Organizer: 55th Annual Meeting of the Society of Toxicology
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2016-03-14
  • Int'l Joint Research
• [Presentation] Innate Effector Mechanisms for Elimination of Human Cancer Cells in the NOD -Background Mice Lacking Adaptive Immunity. (2016)
  • Author(s): Nishime C, Kawai K, Yamamoto T, Katano I, Monnai M, Goda N, Mizushima T, Suemizu H, Nakamura M, Murata M, Suematsu M, Wakui M.
  • Organizer: 5th International Workshop on Humanized Mice
  • Place of Presentation: Zurich,Switzerland
  • Year and Date: 2016-01-28
  • Int'l Joint Research
• [Presentation] Comparison of Human Cell Engraftment and Differentiation Abilities among Strains of Immunodeficient Mice with Different Genetic Backgrounds (2015)
  • Author(s): H.Tsutsumi, S.Kusakawa, R.Sawada, K.Urano, T.Mizushima, E.Nishinaka, R.Inoue, S.Yasuda, and Y.Sato.
  • Organizer: 51st Congress of the European Societies of Toxicology Bridging Sciences for Safety
  • Place of Presentation: Porto, Portugal
  • Year and Date: 2015-09-13
  • Int'l Joint Research
• [Presentation] A luciferin analog achieves highly sensitive deep-tissue tumor imaging using near-infrared bioluminescence (2015)
  • Author(s): Takahiro Kuchimaru, Satoshi Iwano, Msahiro Kiyama, Shun Mitsumata, Tetsuya Kadonosono, Haruki Niwa, Shojiro Maki, Shinae Kizaka-Kondoh
  • Organizer: World Molecular Imaging Congress 2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-09-02
  • Int'l Joint Research
• [Presentation] Intratumoral activity of hypoxia-inducible factors is an excellent marker for targeting malignant tumors. (2015)
  • Author(s): Kizaka-Kondoh S
  • Organizer: Aso International Meeting
  • Place of Presentation: Aso, Kumamoto, Japan
  • Year and Date: 2015-05-14
  • Int'l Joint Research / Invited
• [Presentation] Exploring malignant process by molecular imaging (2014)
  • Author(s): Shinae Kondoh, Tetsuya Kadonosono, Takahiro Kuchimaru
  • Organizer: The 73rd Annual Meeting of JCA
  • Place of Presentation: Pacifico Yokohama, Yokohama
  • Year and Date: 2014-09-27
  • Invited
• [Presentation] In vivo imag-guided screeningによる治療標的の探索 (2014)
  • Author(s): 近藤科江
  • Organizer: 金沢女性がん研究者フォーラム
  • Place of Presentation: 金沢大学、金澤
  • Year and Date: 2014-07-30
  • Invited
• [Presentation] rasH2ﾏｳスの発がん感受性保証のための長期ﾓﾆﾀﾘﾝｸ (2014)
  • Author(s): 浦野浩司、町田一彦、水島友子、西銘千代子、西中栄子、井上亮、伊東一昭、保田昌彦、堤秀樹
  • Organizer: 第41回日本毒性学会学術年会
  • Place of Presentation: 神戸コンベンションセンター、神戸
  • Year and Date: 2014-07-02 – 2014-07-04
• [Presentation] 精子成熟因子としての自然免疫因子リポカリン2 (2014)
  • Author(s): 渡邊 仁美、竹尾 透、東城 博雅、酒匂 一仁、中潟 直己、Tak W. Mak、近藤 玄
  • Organizer: 第６１回日本実験動物学会
  • Place of Presentation: 札幌コンベンションセンター,札幌
  • Year and Date: 2014-05-15 – 2014-05-17
• [Presentation] がんの悪性化指標としての低酸素誘導転写因子HIF活性 (2014)
  • Author(s): 近藤科江
  • Organizer: 第103回 日本病理学会総会
  • Place of Presentation: 広島国際会議場、広島
  • Year and Date: 2014-04-24
  • Invited
• [Presentation] 腫瘍内微小環境のインビボ光イメージング (2014)
  • Author(s): 近藤科江
  • Organizer: 新学術領域ナノメディシン分子科学シンポジウム
  • Place of Presentation: 東京工業大学、横浜
  • Year and Date: 2014-04-22
  • Invited
• [Presentation] Significance of hypoxia-inducible factor activity during tumor development and malignant progression. (2014)
  • Author(s): Shinae Kondoh, Takahiro Kuchimaru, Tetsuya Kadonosono.
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Miyakomesse, Kyoto
  • Year and Date: 2014-04-14 – 2014-04-17
  • Invited
• [Presentation] HIF活性を標的としたがんのイメージングとターゲティング (2013)
  • Author(s): 近藤科江、口丸高広、門之園哲哉
  • Organizer: 第１回 がんと代謝研究会
  • Place of Presentation: 慶應義塾大学先端生命科学研究所、鶴岡
  • Year and Date: 2013-10-31
  • Invited
• [Book] 腫瘍内HIF活性のin vivo イメージング (2015)
  • Author(s): 近藤科江、口丸高弘、門之園哲哉
  • Total Pages: 12
  • Publisher: 化学同人
• [Book] がん間質における低酸素応答が悪性化を駆動する (2015)
  • Author(s): 近藤科江、口丸高弘、門之園哲哉
  • Total Pages: 7
  • Publisher: 羊土社
• [Book] 腫瘍内微小環境を標的とした薬剤開発の留意点 (2015)
  • Author(s): 近藤科江
  • Total Pages: 9
  • Publisher: 技術情報協会
• [Book] がん基盤生物学 (2013)
  • Author(s): 近藤科江 他
  • Total Pages: 336
  • Publisher: 南山堂
• [Book] 血管新生研究の最先端 (2013)
  • Author(s): 近藤科江 他
  • Total Pages: 331
  • Publisher: 医薬ジャーナル社
• [Remarks] 東京工業大学近藤研究室HP: がん微小環境の可視化による病態イメージングツールの開発
  • URL: http://www.kondohlab.bio.titech.ac.jp/research
• [Remarks] がん微小環境を可視化する発光イメージングツールの開発
  • URL: http://www.kondohlab.bio.titech.ac.jp/research
• [Remarks] 東工大近藤研＞Research＞がん微小環境を可視化する発光イメージングツールの開発
  • URL: http://www.kondohlab.bio.titech.ac.jp/research
• [Patent(Industrial Property Rights)] An easy, fast and low-cost screening technology of peptides with high affinity and avidity for target molecules (2014)
  • Inventor(s): Kadonosono T, Kizaka-Kondoh S
  • Industrial Property Rights Holder: 東京工業大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-04-23
  • Overseas