Updated on 2024/10/07

Information

 

写真a

 
KUBA KEIJI
 
Organization
Faculty of Medical Sciences Department of Basic Medicine Professor
School of Medicine Department of Medicine(Concurrent)
Graduate School of Medical Sciences Department of Medicine(Concurrent)
Graduate School of Medical Sciences Department of Health Care Administration and Management(Concurrent)
Title
Professor
Contact information
メールアドレス
Tel
0926426080
Profile
循環器・呼吸器疾患や新型コロナ感染症の病態形成におけるRNA制御とシグナル伝達の分子機構の解明研究ならびに創薬応用開発を目指した研究

Research Areas

  • Life Science / Pharmacology

Degree

  • Medical Science

Research History

  • 2007年3月 東京医科歯科大学難治疾患研究所 特任講師 2008年12月 秋田大学大学院医学系研究科 情報制御学・実験治療学講座 准教授 2014年8月 秋田大学大学院医学系研究科 分子機能学・代謝機能学講座 教授

Research Interests・Research Keywords

  • Research theme:heart failure

    Keyword:heart failure

    Research period: 2024

  • Research theme:アンジオテンシン変換酵素2 (ACE2)

    Keyword:アンジオテンシン変換酵素2 (ACE2)

    Research period: 2024

  • Research theme:tumor heterogeneity

    Keyword:tumor heterogeneity

    Research period: 2024

  • Research theme:TLR4

    Keyword:TLR4

    Research period: 2024

  • Research theme:RNA分解

    Keyword:RNA分解

    Research period: 2024

  • Research theme:RNAメチル化

    Keyword:RNAメチル化

    Research period: 2024

  • Research theme:Protectin D1

    Keyword:Protectin D1

    Research period: 2024

  • Research theme:NPY

    Keyword:NPY

    Research period: 2024

  • Research theme:Galectin-7

    Keyword:Galectin-7

    Research period: 2024

  • Research theme:CNOT3

    Keyword:CNOT3

    Research period: 2024

  • Research theme:CCR4-NOT複合体

    Keyword:CCR4-NOT複合体

    Research period: 2024

  • Research theme:Apelin

    Keyword:Apelin

    Research period: 2024

  • Research theme:Elucidation of pathophysiological mechanisms of cancer-related cardiovascular and respiratory dysfunction mediated by RNA regulation

    Keyword:doxorubicin, heart failure, bleomycin, respiratory failure

    Research period: 2023.8

  • Research theme:Elucidation of the pathogenesis of spatio-temporal exacerbation and aftereffects of highly pathogenic viral respiratory infections

    Keyword:SARS-CoV-2, ACE2, ARDS, brain infection

    Research period: 2023.8

  • Research theme:Elucidation of the RNA degradation and transcriptional regulation-mediated pathogenesis of cardiovascular diseases and its therapeutic applications

    Keyword:CCR4-NOT complex, poly(A), m6A methylation, heart failure

    Research period: 2023.8

  • Research theme:Development of new prediction and treatment methods for cancer metastasis by spatial tumor heterogeneity of highly metastatic tumors

    Keyword:galectin, tumor immunity, squamous cell carcinoma

    Research period: 2023.8

Papers

  • Squamous cell carcinoma‐derived <scp>G‐CSF</scp> promotes tumor growth and metastasis in mice through neutrophil recruitment and tumor cell proliferation, associated with poor prognosis of the patients

    Kohei Kemuriyama, Jianbo An, Satoru Motoyama, Yushi Nagaki, Tomokazu Yamaguchi, Yusuke Sato, Akiyuki Wakita, Yoshihiro Minamiya, Keiji Kuba

    Genes to Cells   28 ( 8 )   573 - 584   2023.5   ISSN:1356-9597 eISSN:1365-2443

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    Language:Others   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    Abstract

    Tumor‐derived G‐CSF is a well‐known factor to aggravate disease progression in various types of cancers. In this study, we investigated a role of G‐CSF in squamous cell carcinoma (SCC). High expression of G‐CSF in the tumor tissues of esophageal SCC (ESCC) patients correlated with poor prognosis. Murine SCC NR‐S1M cells produce considerable amount of G‐CSF, which expression is correlated with its metastatic potentials. Deletion of G‐CSF in NR‐S1M cells mitigated tumor growth and metastasis to lymph node and lung of subcutaneous NR‐S1M tumors in the mice. Mechanistically, G‐CSF enhanced cell proliferation in autocrine manner in vitro, whereas in NR‐S1M tumor‐bearing mice, accumulation of plasma G‐CSF was associated with expansion of peripheral neutrophils, which led to a decreased proportion of CD8<sup>+</sup> T cells. Antibody depletion of neutrophils restored the number of CD8+ T cells and modestly suppressed tumor outgrowth, albeit no changes in distant metastasis. We propose that G‐CSF produced by NR‐S1M cells facilitates tumor progression in mice through bi‐functional effects to promote neutrophil recruitment and tumor cell proliferation, which may render poor prognosis to the ESCC patients with high G‐CSF expression.

    DOI: 10.1111/gtc.13051

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  • Identification of Galectin-7 as a crucial metastatic enhancer of squamous cell carcinoma associated with immunosuppression

    Jianbo An, Yushi Nagaki, Satoru Motoyama, Yuta Kuze, Midori Hoshizaki, Kohei Kemuriyama, Tomokazu Yamaguchi, Takashi Ebihara, Yoshihiro Minamiya, Yutaka Suzuki, Yumiko Imai, Keiji Kuba

    Oncogene   41 ( 50 )   5319 - 5330   2022.12   ISSN:0950-9232 eISSN:1476-5594

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    DOI: 10.1038/s41388-022-02525-1

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    Other Link: https://www.nature.com/articles/s41388-022-02525-1

  • ACE2-like enzyme B38-CAP suppresses abdominal sepsis and severe acute lung injury. Invited Reviewed International journal

    Minato T, Yamaguchi T, Hoshizaki M, Nirasawa S, An J, Takahashi S, Penninger JM, Imai Y, Kuba K.

    PLoS One   17 ( 7 )   2022.7

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  • ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury. International journal

    Tomokazu Yamaguchi, Midori Hoshizaki, Takafumi Minato, Satoru Nirasawa, Masamitsu N Asaka, Mayumi Niiyama, Masaki Imai, Akihiko Uda, Jasper Fuk-Woo Chan, Saori Takahashi, Jianbo An, Akari Saku, Ryota Nukiwa, Daichi Utsumi, Maki Kiso, Atsuhiro Yasuhara, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Yuji Fujino, Satoru Motoyama, Satoshi Nagata, Josef M Penninger, Haruhiko Kamada, Kwok-Yung Yuen, Wataru Kamitani, Ken Maeda, Yoshihiro Kawaoka, Yasuhiro Yasutomi, Yumiko Imai, Keiji Kuba

    Nature communications   12 ( 1 )   6791 - 6791   2021.11

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    DOI: 10.1038/s41467-021-27097-8

  • Highly susceptible SARS-CoV-2 model in CAG promoter-driven hACE2 transgenic mice

    Masamitsu N. Asaka, Daichi Utsumi, Haruhiko Kamada, Satoshi Nagata, Yutaka Nakachi, Tomokazu Yamaguchi, Yoshihiro Kawaoka, Keiji Kuba, Yasuhiro Yasutomi

    JCI Insight   2021.8

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    DOI: 10.1172/jci.insight.152529

  • The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation. International journal

    Akinori Takahashi, Toru Suzuki, Shou Soeda, Shohei Takaoka, Shungo Kobori, Tomokazu Yamaguchi, Haytham Mohamed Aly Mohamed, Akiko Yanagiya, Takaya Abe, Mayo Shigeta, Yasuhide Furuta, Keiji Kuba, Tadashi Yamamoto

    Life science alliance   3 ( 5 )   2020.5

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    DOI: 10.26508/lsa.201900494

  • B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction. Reviewed International journal

    Takafumi Minato, Satoru Nirasawa, Teruki Sato, Tomokazu Yamaguchi, Midori Hoshizaki, Tadakatsu Inagaki, Kazuhiko Nakahara, Tadashi Yoshihashi, Ryo Ozawa, Saki Yokota, Miyuki Natsui, Souichi Koyota, Taku Yoshiya, Kumiko Yoshizawa-Kumagaye, Satoru Motoyama, Takeshi Gotoh, Yoshikazu Nakaoka, Josef M Penninger, Hiroyuki Watanabe, Yumiko Imai, Saori Takahashi, Keiji Kuba

    Nature communications   11 ( 1 )   1058 - 1058   2020.2

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    DOI: 10.1038/s41467-020-14867-z

  • Genome-Scale CRISPR/Cas9 Screening Reveals Squalene Epoxidase as a Susceptibility Factor for Cytotoxicity of Malformin A1. Reviewed International journal

    20 ( 12 )   1563 - 1568   2019.6

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    DOI: 10.1002/cbic.201800769

  • Pulmonary phagocyte-derived NPY controls the pathology of severe influenza virus infection. Reviewed

    Fujiwara S, Hoshizaki M, Ichida Y, Lex D, Kuroda E, Ishii KJ, Magi S, Okada M, Takao H, Gandou M, Imai H, Hara R, Herzog H, Yoshimura A, Okamura H, Penninger JM, Slutsky AS, Uhlig S, Kuba K, Imai Y

    Nature microbiology   4 ( 2 )   258 - 268   2019.2

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    Pulmonary phagocyte-derived NPY controls the pathology of severe influenza virus infection.
    © 2018, The Author(s), under exclusive licence to Springer Nature Limited. Crosstalk between the autonomic nervous system and the immune system by means of the sympathetic and parasympathetic pathways is a critical process in host defence. Activation of the sympathetic nervous system results in the release of catecholamines as well as neuropeptide Y (NPY). Here, we investigated whether phagocytes are capable of the de novo production of NPY, as has been described for catecholamines. We show that the synthesis of NPY and its Y1 receptor (Y1R) is increased in phagocytes in lungs following severe influenza virus infection. The genetic deletion of Npy or Y1r specifically in phagocytes greatly improves the pathology of severe influenza virus infection, which is characterized by excessive virus replication and pulmonary inflammation. Mechanistically, it is the induction of suppressor of cytokine signalling 3 (SOCS3) via NPY–Y1R activation that is responsible for impaired antiviral response and promoting pro-inflammatory cytokine production, thereby enhancing the pathology of influenza virus infection. Thus, direct regulation of the NPY–Y1R–SOCS3 pathway on phagocytes may act as a fine-tuner of an innate immune response to virus infection, which could be a therapeutic target for lethal influenza virus infection.

    DOI: 10.1038/s41564-018-0289-1

  • Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling. Reviewed International journal

    Sato T, Kadowaki A, Suzuki T, Ito H, Watanabe H, Imai Y, Kuba K

    International journal of molecular sciences   20 ( 2 )   2019.1

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    Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling.
    Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1⁻7-dependent manner. Whether apelin antagonizes the over-activation of the renin⁻angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-β) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.

    DOI: 10.3390/ijms20020239

  • The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function. Reviewed International journal

    Tomokazu Yamaguchi, Takashi Suzuki, Teruki Sato, Akinori Takahashi, Hiroyuki Watanabe, Ayumi Kadowaki, Miyuki Natsui, Hideaki Inagaki, Satoko Arakawa, Shinji Nakaoka, Yukio Koizumi, Shinsuke Seki, Shungo Adachi, Akira Fukao, Toshinobu Fujiwara, Tohru Natsume, Akinori Kimura, Masaaki Komatsu, Shigeomi Shimizu, Hiroshi Ito, Yutaka Suzuki, Josef M Penninger, Tadashi Yamamoto, Yumiko Imai, Keiji Kuba

    Science signaling   11 ( 516 )   2018.2

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    DOI: 10.1126/scisignal.aan3638

  • Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives Reviewed

    Laina Freyer, Chih-Wei Hsu, Sonja Nowotschin, Andrea Pauli, Junji Ishida, Keiji Kuba, Akiyoshi Fukamizu, Alexander F. Schier, Pamela A. Hoodless, Mary E. Dickinson, Anna-Katerina Hadjantonakis

    CELL REPORTS   20 ( 9 )   2116 - 2130   2017.8

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    DOI: 10.1016/j.celrep.2017.08.014

  • ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage Reviewed

    Teruki Sato, Chitose Sato, Ayumi Kadowaki, Hiroyuki Watanabe, Lena Ho, Junji Ishida, Tomokazu Yamaguchi, Akinori Kimura, Akiyoshi Fukamizu, Josef M. Penninger, Bruno Reversade, Hiroshi Ito, Yumiko Imai, Keiji Kuba

    CARDIOVASCULAR RESEARCH   113 ( 7 )   760 - 769   2017.6

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    DOI: 10.1093/cvr/cvx061

  • Interaction of CCR4-NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis Reviewed

    Cheng-Yuan Yang, Senthilkumar Ramamoorthy, Soeren Boller, Marc Rosenbaum, Alfonso Rodriguez Gil, Gerhard Mittler, Yumiko Imai, Keiji Kuba, Rudolf Grosschedl

    GENES & DEVELOPMENT   30 ( 20 )   2310 - 2324   2016.10

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    DOI: 10.1101/gad.285452.116

  • Apelin is a positive regulator of ACE2 in failing hearts Reviewed

    Teruki Sato, Takashi Suzuki, Hiroyuki Watanabe, Ayumi Kadowaki, Akiyoshi Fukamizu, Peter P. Liu, Akinori Kimura, Hiroshi Ito, Josef M. Penninger, Yumiko Imai, Keiji Kuba

    JOURNAL OF CLINICAL INVESTIGATION   123 ( 12 )   5203 - 5211   2013.12

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    DOI: 10.1172/JCI69608

  • The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza Reviewed

    Masayuki Morita, Keiji Kuba, Akihiko Ichikawa, Mizuho Nakayama, Jun Katahira, Ryo Iwamoto, Tokiko Watanebe, Saori Sakabe, Tomo Daidoji, Shota Nakamura, Ayumi Kadowaki, Takayo Ohto, Hiroki Nakanishi, Ryo Taguchi, Takaaki Nakaya, Makoto Murakami, Yoshihiro Yoneda, Hiroyuki Arai, Yoshihiro Kawaoka, Josef M. Penninger, Makoto Arita, Yumiko Imai

    Cell   153 ( 1 )   112 - 125   2013.3

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    DOI: 10.1016/j.cell.2013.02.027

  • CXCL10-CXCR3 Enhances the Development of Neutrophil-mediated Fulminant Lung Injury of Viral and Nonviral Origin Reviewed

    Akihiko Ichikawa, Keiji Kuba, Masayuki Morita, Shinsuke Chida, Hiroyuki Tezuka, Hiromitsu Hara, Takehiko Sasaki, Toshiaki Ohteki, V. Marco Ranieri, Claudia C. dos Santos, Yoshihiro Kawaoka, Shizuo Akira, Andrew D. Luster, Bao Lu, Josef M. Penninger, Stefan Uhlig, Arthur S. Slutsky, Yumiko Imai

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   187 ( 1 )   65 - 77   2013.1

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    DOI: 10.1164/rccm.201203-0508OC

  • CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin. Reviewed

    Akihiko Ichikawa, Keiji Kuba, Masayuki Morita, Shinsuke Chida, Hiroyuki Tezuka, Hiromitsu Hara, Takehiko Sasaki, Toshiaki Ohteki, V Marco Ranieri, Claudia C dos Santos, Yoshihiro Kawaoka, Shizuo Akira, Andrew D Luster, Bao Lu, Josef M Penninger, Stefan Uhlig, Arthur S Slutsky, Yumiko Imai

    Am. J. Respir. Crit. Care Med.   187 ( 1 )   65 - 77   2013.1

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    CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin.
    Patients who developed acute respiratory distress syndrome (ARDS) after infection with severe respiratory viruses (e.g., severe acute respiratory syndrome-coronavirus, H5N1 avian influenza virus), exhibited unusually high levels of CXCL10, which belongs to the non-ELR (glutamic-leucine-arginine) CXC chemokine superfamily. CXCL10 may not be a bystander to the severe virus infection but may directly contribute to the pathogenesis of neutrophil-mediated, excessive pulmonary inflammation.<br />
    We investigated the contribution of CXCL10 and its receptor CXCR3 axis to the pathogenesis of ARDS with nonviral and viral origins.<br />
    We induced nonviral ARDS by acid aspiration and viral ARDS by intratracheal influenza virus infection in wild-type mice and mice deficient in CXCL10, CXCR3, IFNAR1 (IFN-α/β receptor 1), or TIR domain-containing adaptor inducing IFN-β (TRIF).<br />
    We found that the mice lacking CXCL10 or CXCR3 demonstrated improved severity and survival of nonviral and viral ARDS, whereas mice that lack IFNAR1 did not control the severity of ARDS in vivo. The increased levels of CXCL10 in lungs with ARDS originate to a large extent from infiltrated pulmonary neutrophils, which express a uniq

    DOI: 10.1164/rccm.201203-0508OC

  • A Global In Vivo Drosophila RNAi Screen Identifies NOT3 as a Conserved Regulator of Heart Function Reviewed

    G. Gregory Neely, Keiji Kuba, Anthony Cammarato, Kazuya Isobe, Sabine Amann, Liyong Zhang, Mitsushige Murata, Lisa Elmen, Vaijayanti Gupta, Suchir Arora, Rinku Sarangi, Debasis Dan, Susumu Fujisawa, Takako Usami, Cui-ping Xia, Alex C. Keene, Nakissa N. Alayari, Hiroyuki Yamakawa, Ulrich Elling, Christian Berger, Maria Novatchkova, Rubina Koglgruber, Keiichi Fukuda, Hiroshi Nishina, Mitsuaki Isobe, J. Andrew Pospisilik, Yumiko Imai, Arne Pfeufer, Andrew A. Hicks, Peter P. Pramstaller, Sai Subramaniam, Akinori Kimura, Karen Ocorr, Rolf Bodmer, Josef M. Penninger

    CELL   141 ( 1 )   142 - 153   2010.4

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    DOI: 10.1016/j.cell.2010.02.023

  • Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury Reviewed

    Yumiko Imai, Keiji Kuba, G. Greg Neely, Rubina Yaghubian-Malhami, Thomas Perkmann, Geert van Loo, Maria Ermolaeva, Ruud Veldhuizen, Y. H. Connie Leung, Hongliang Wang, Haolin Liu, Yang Sun, Manolis Pasparakis, Manfred Kopf, Christin Mech, Sina Bavari, J. S. Malik Peiris, Arthur S. Slutsky, Shizuo Akira, Malin Hultqvist, Rikard Holmdahl, John Nicholls, Chengyu Jiang, Christoph J. Binder, Josef M. Penninger

    CELL   133 ( 2 )   235 - 249   2008.4

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    DOI: 10.1016/j.cell.2008.02.043

  • Impaired heart Contractility in apelin gene-deficient mice associated with aging and pressure overload Reviewed

    Keiji Kuba, Liyong Zhang, Yumiko Imai, Sara Arab, Manyin Chen, Yuichiro Maekawa, Michael Leschnik, Andreas Leibbrandt, Mato Makovic, Julia Schwaighofer, Nadine Beetz, Renata Musialek, G. Greg Neely, Vukoslav Komnenovic, Ursula Kolm, Bernhard Metzler, Romeo Ricci, Hiromitsu Hara, Arabella Meixner, Mai Nghiem, Xin Chen, Fayez Dawood, Kit Man Wong, Renu Sarao, Eva Cukerman, Akinori Kimura, Lutz Hein, Johann Thalhammer, Peter P. Liu, Josef M. Penninger

    CIRCULATION RESEARCH   101 ( 4 )   E32 - E42   2007.8

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    DOI: 10.1161/CIRCRESAHA.107.158659

  • A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury Reviewed

    K Kuba, Y Imai, SA Rao, H Gao, F Guo, B Guan, Y Huan, P Yang, YL Zhang, W Deng, LL Bao, BL Zhang, G Liu, Z Wang, M Chappell, YX Liu, DX Zheng, A Leibbrandt, T Wada, AS Slutsky, DP Liu, CA Qin, CY Jiang, JM Penninger

    NATURE MEDICINE   11 ( 8 )   875 - 879   2005.8

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    DOI: 10.1038/nm1267

  • Angiotensin-converting enzyme 2 protects from severe acute lung failure Reviewed

    Y Imai, K Kuba, S Rao, Y Huan, F Guo, B Guan, P Yang, R Sarao, T Wada, H Leong-Poi, MA Crackower, A Fukamizu, CC Hui, L Hein, S Uhlig, AS Slutsky, CY Jiang, JM Penninger

    NATURE   436 ( 7047 )   112 - 116   2005.7

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    DOI: 10.1038/nature03712

  • Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model Reviewed

    Daisaku Tomioka, Naoki Maehara, Keiji Kuba, Kazuhiro Mizumoto, Masao Tanaka, Kunio Matsumoto, Toshikazu Nakamura

    Cancer Research   61 ( 20 )   7518 - 7524   2001.10

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  • Kringle 1-4 of hepatocyte growth factor inhibits proliferation and migration of human microvascular endothelial cells Reviewed

    Keiji Kuba, Kunio Matsumoto, Kenji Ohnishi, Takayuki Shiratsuchi, Masao Tanaka, Toshikazu Nakamura

    Biochemical and Biophysical Research Communications   279 ( 3 )   846 - 852   2000.12

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    DOI: 10.1006/bbrc.2000.4034

  • HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Invited Reviewed International journal

    Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M, Nakamura T

    Cancer Research   2000.1

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  • Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer. International journal

    Koki Oyama, Kohei Nakata, Chikanori Tsutsumi, Masataka Hayashi, Bo Zhang, Yuki Mochida, Tomohiko Shinkawa, Kento Hirotaka, Pingshan Zhong, Satomi Date, Haizhen Luo, Akihiro Kubo, Nobuhiro Higashijima, Yutaka Yamada, Toshiya Abe, Noboru Ideno, Kazuhiro Koikawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Hideya Onishi, Takashi Morisaki, Keiji Kuba, Yoshinao Oda, Masafumi Nakamura

    Cancer research   2024.9   ISSN:0008-5472

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    The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment (TIME). Autophagy, which has been shown to play a role in anti-tumor immunity, has been proposed as a therapeutic target for PDAC. Here, single-cell RNA-sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy inhibition in cancer cells induced dendritic cell (DC) activation. Analysis of human PDAC tumors substantiated a negative correlation between autophagy and DC activation signatures. Mechanistically, autophagy inhibition increased intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine (CQ), an autophagy inhibitor, in combination with Flt3 ligand (Flt3L)-induced DC infiltration inhibited tumor growth and increased tumor-infiltrating T lymphocytes. However, autophagy inhibition in cancer cells also induced CD8+ T cell exhaustion with high expression of immune checkpoint LAG3. A triple therapy comprising CQ, Flt3L, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models. Thus, targeting autophagy in cancer cells and activating DCs sensitizes PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer.

    DOI: 10.1158/0008-5472.CAN-24-0830

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  • eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition. International journal

    Yuichi Shichino, Tomokazu Yamaguchi, Kazuhiro Kashiwagi, Mari Mito, Mari Takahashi, Takuhiro Ito, Nicholas T Ingolia, Keiji Kuba, Shintaro Iwasaki

    Nature structural & molecular biology   2024.5   ISSN:1545-9993 eISSN:1545-9985

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    Eukaryotic translation initiation factor (eIF)4A-a DEAD-box RNA-binding protein-plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs, whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the interaction between TOP mRNAs and LARP1 and, thus, ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator.

    DOI: 10.1038/s41594-024-01321-7

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  • Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells. International journal

    PingShan Zhong, Kohei Nakata, Koki Oyama, Nobuhiro Higashijima, Akiko Sagara, Satomi Date, HaiZhen Luo, Masataka Hayashi, Akihiro Kubo, ChenYi Wu, Shan He, Takeo Yamamoto, Kazuhiro Koikawa, Chika Iwamoto, Toshiya Abe, Naoki Ikenaga, Kenoki Ohuchida, Takashi Morisaki, Yoshinao Oda, Keiji Kuba, Masafumi Nakamura

    Journal of experimental & clinical cancer research : CR   43 ( 1 )   138 - 138   2024.5   ISSN:0392-9078 eISSN:1756-9966

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    BACKGROUND: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. METHODS: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. RESULTS: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. CONCLUSIONS: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

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  • Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells. Invited Reviewed International journal

    Zhong P, Nakata K, Oyama K, Higashijima N, Sagara A, Date S, Luo H, Hayashi M, Kubo A, Wu C, He S, Yamamoto T, Koikawa K, Iwamoto C, Abe T, Ikenaga N, Ohuchida K, Morisaki T, Oda Y, Kuba K, Nakamura M.

    Journal of Experimental & Clinical Cancer Research   43 ( 1 )   2024.5

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  • Haploinsufficiency of Cnot3 Aggravates Acid-Induced Acute Lung Injury Likely Through Transcriptional and Post-Transcriptional Upregulation of Pro-Inflammatory Genes. International journal

    Tomokazu Yamaguchi, Ryo Ozawa, Takafumi Minato, Midori Hoshizaki, Yutaro Kammura, Kazuma Okawara, Yousef A Khalil, Masafumi Nakamura, Ken Yamaura, Masayuki Fukuda, Yumiko Imai, Keiji Kuba

    Journal of inflammation research   17   5415 - 5425   2024   ISSN:1178-7031 eISSN:1178-7031

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    BACKGROUND: Acute lung injury (ALI) is caused by a variety of illnesses, including aspiration pneumonia and sepsis. The CCR4-NOT complex is a large multimeric protein complex that degrades mRNA through poly(A) tail shortening, whereas it also contributes to regulation of transcription and translation. Cnot3 is a scaffold component of the CCR4-NOT complex and is essential for the integrity of the complex; loss of Cnot3 leads to depletion of whole complex. While the significance of cytokine mRNA degradation in limiting inflammation has been established, the roles of CCR4-NOT complex-mediated in ALI remain elusive. METHODS: The effects of Cnot3 haploinsufficiency in the pathology and cytokine expression were analyzed in the mouse lungs of acid aspiration-induced acute lung injury. The decay rate and transcription activity of cytokine mRNAs under Cnot3 heterozygous deletion were analyzed in lipopolysaccharide (LPS) -stimulated mouse embryonic fibroblasts (MEFs). RESULTS: Tamoxifen-induced heterozygous deletion of Cnot3 in adult mice (Cnot3 Hetz) did not show body weight loss or any apparent abnormality. Under acid aspiration-induced acute lung injury, Cnot3 Hetz mice exhibited increased pulmonary edema, worse lung pathologies and more severe inflammation compared with wild type mice. mRNA expression of pro-inflammatory genes Il1b and Nos2 were significantly upregulated in the lungs of Cnot3 Hetz mice. Consistently, mRNA expression of Il1b and Nos2 was upregulated in LPS-stimulated Cnot3 Hetz MEFs. Mechanistically, while heterozygous depletion of Cnot3 stabilized both Il1b and Nos2 mRNAs, the nascent pre-mRNA level of Il1b was upregulated in Cnot3 Hetz MEFs, implicating Cnot3-mediated transcriptional repression of Il1b expression in addition to destabilization of Il1b and Nos2 mRNAs. PU.1 (Spi1) was identified as a causative transcription factor to promote Il1b expression under Cnot3 haploinsufficient conditions. CONCLUSION: CNOT3 plays a protective role in ALI by suppressing expression of pro-inflammatory genes Il1b and Nos2 through both post-transcriptional and transcriptional mechanisms, including mRNA stability control of Spi1.

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  • TIGIT mediates activation-induced cell death of ILC2s during chronic airway allergy. International journal

    Toshiki Yamada, Megumi Tatematsu, Shunsuke Takasuga, Akane Fuchimukai, Kenki Yamagata, Shinsuke Seki, Keiji Kuba, Hideyuki Yoshida, Ichiro Taniuchi, Günter Bernhardt, Kazuko Shibuya, Akira Shibuya, Takechiyo Yamada, Takashi Ebihara

    The Journal of experimental medicine   220 ( 7 )   2023.7

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    While group-2 innate lymphoid cells (ILC2s) are highly proliferative in allergic inflammation, the removal of overactivated ILC2s in allergic diseases has not been investigated. We previously showed that chronic airway allergy induces "exhausted-like" dysfunctional ILC2s expressing T cell immunoreceptor with Ig and ITIM domains (TIGIT). However, the physiological relevance of these cells in chronic allergy remains elusive. To precisely identify and monitor TIGIT+ ILC2s, we generated TIGIT lineage tracer mice. Chronic allergy stably induced TIGIT+ ILC2s, which were highly activated, apoptotic, and were quickly removed from sites of chronic allergy. Transcripts from coding genes were globally suppressed in the cells, possibly due to reduced chromatin accessibility. Cell death in TIGIT+ ILC2s was enhanced by interactions with CD155 expressed on macrophages, whereas genetic ablation of Tigit or blockade by anti-TIGIT antagonistic antibodies promoted ILC2 survival, thereby deteriorating chronic allergic inflammation. Our work demonstrates that TIGIT shifts the fate of ILC2s toward activation-induced cell death, which could present a new therapeutic target for chronic allergies.

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  • Apelin expression is downregulated in T cells in a murine model of chronic colitis. International journal

    Daiki Yamada, Yudai Kojima, Akinori Hosoya, Masahiro Suzuki, Taro Watabe, Tadahiko Inoue, Naoya Tsugawa, Takehito Asakawa, Yuki Yonemoto, Michio Onizawa, Yasuhiro Nemoto, Shigeru Oshima, Motoyuki Shimonaka, Keiji Kuba, Junji Ishida, Akiyoshi Fukamizu, Josef M Penninger, Mamoru Watanabe, Ryuichi Okamoto, Takashi Nagaishi

    Biochemical and biophysical research communications   647   72 - 79   2023.3   ISSN:0006-291X eISSN:1090-2104

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    Apelin (APL), an endogenous ligand for APJ, has been reported to be upregulated in a murine model of acute colitis induced by sodium dextran sulfate, as well as inflammatory bowel diseases (IBD) in humans. However, the mechanisms and functions of APL/APJ axis in the pathogenesis of IBD are unclear. We herein analyzed CD4+ T cells to determine the functions of APL in a murine model of chronic colitis induced in Rag deficient mice (Rag-/-). In colonic tissues of wild-type mice (WT), we found that APL was expressed especially in the lamina propria lymphocytes, where CD4+ T cells are dominant, rather than the epithelial cells. Unexpectedly, the APL expression was rather downregulated in the colonic tissue of the chronic colitis group compared to the control groups (Rag-/- before colitis induction and WT). The APL expression was downregulated when naïve T cells were differentiated into effecter T cells. A lack of APL resulted in decreased naïve T cells and increased effecter T cells in secondary lymphoid organs. A synthetic APL peptide, [Pyr1]-APL-13, increased IL-10 and decreased IFN-γ productions by effecter T cells. Administration of [Pyr1]-APL-13 improved survival rate in association with lessened colitis severity and decreased pro-inflammatory cytokine production. This is the first report showing immunological function of APL specifically on T cells, and these results indicate that APL/APJ axis may be a novel therapeutic target for IBD.

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  • Peritumoral CD16b positive-neutrophil accumulation strongly correlates with regional lymph node metastasis in thoracic esophageal squamous cell cancer. International journal

    Hiromu Fujita, Satoru Motoyama, Jianbo An, Yushi Nagakai, Tomokazu Yamaguchi, Souichi Koyota, Yusuke Sato, Akiyuki Wakita, Kazuhiro Imai, Keiji Kuba, Yoshihiro Minamiya

    Surgery   171 ( 6 )   1535 - 1542   2022.6

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    BACKGROUND: The mechanism underlying cancer cell metastasis from the tumor to regional lymph nodes is not yet fully understood. We hypothesized that peritumoral neutrophil accumulation promotes regional lymph node metastasis in thoracic esophageal squamous cell cancer. METHODS: Between 2010 and 2019, 126 thoracic esophageal squamous cell cancer patients received curative (R0) esophagectomy without preoperative treatment in our hospital. Using paraffin-embedded resected tumors, we performed immunohistochemical analysis of CD16b-positive neutrophil accumulation in the peritumoral area, which was defined as a 1-mm region centered on the border separating the malignant cell nests from the host tissue. The relationship between the density of peritumoral CD16b staining and pathological lymph node metastasis or 5-year overall survival was evaluated. RESULTS: Although the clinicopathological characteristics of CD16b-high and CD16b-low patients did not differ, greater pathological lymph node metastasis (P < .001) and lymphatic invasion by the tumor (P = .024) and a poorer 5-year survival (P = .010) were seen in CD16b-high patients. Moreover, CD16b-positive neutrophil density was generally higher in the peritumoral area than within the tumor itself. Univariate and multivariate analyses showed that CD16b-positive neutrophil accumulation was an independent factor for lymph node metastasis with an odds ratio >25 (P < .001). On the other hand, blood neutrophil counts did not correlate with lymph node metastasis. CONCLUSION: Peritumoral accumulation of CD16b-positive neutrophils is an independent factor strongly correlated with lymph node metastasis in thoracic esophageal squamous cell cancer.

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  • ACE2-like enzyme B38-CAP suppresses abdominal sepsis and severe acute lung injury. International journal

    Takafumi Minato, Tomokazu Yamaguchi, Midori Hoshizaki, Satoru Nirasawa, Jianbo An, Saori Takahashi, Josef M Penninger, Yumiko Imai, Keiji Kuba

    PloS one   17 ( 7 )   e0270920   2022

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    Angiotensin-converting enzyme 2 (ACE2) is the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and improves the pathologies of cardiovascular disease and acute respiratory distress syndrome (ARDS)/acute lung injury. B38-CAP is a bacteria-derived ACE2-like carboxypeptidase as potent as human ACE2 and ameliorates hypertension, heart failure and SARS-CoV-2-induced lung injury in mice. Recombinant B38-CAP is prepared with E. coli protein expression system more efficiently than recombinant soluble human ACE2. Here we show therapeutic effects of B38-CAP on abdominal sepsis- or acid aspiration-induced acute lung injury. ACE2 expression was downregulated in the lungs of mice with cecal ligation puncture (CLP)-induced sepsis or acid-induced lung injury thereby leading to upregulation of Ang II levels. Intraperitoneal injection of B38-CAP significantly decreased Ang II levels while upregulated angiotensin 1-7 levels. B38-CAP improved survival rate of the mice under sepsis. B38-CAP suppressed the pathologies of lung inflammation, improved lung dysfunction and downregulated elevated cytokine mRNA levels in the mice with acute lung injury. Thus, systemic treatment with an ACE2-like enzyme might be a potential therapeutic strategy for the patients with severe sepsis or ARDS.

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  • Therapeutic effects of angiotensin converting enzyme 2 (ACE2) enzyme activity on acute lung injury in COVID-19

    Tomokazu Yamaguchi, Midori Hoshizaki, Takafumi Minato, Satoru Nirasawa, Masamitsu Asaka, Mayumi Niiyama, Jianbo An, Daichi Utsumi, Satoshi Nagata, Haruhiko Kamada, Wataru Kamitani, Yoshihiro Kawaoka, Yasuhiro Yasutomi, Yumiko Imai, Keiji Kuba

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   95   2 - O   2022   eISSN:2435-4953

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  • Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection Reviewed

    Kwang Su Kim, Shoya Iwanami, Takafumi Oda, Yasuhisa Fujita, Keiji Kuba, Taiga Miyazaki, Keisuke Ejima, Shingo Iwami

    Life Science Alliance   4 ( 10 )   e202101049 - e202101049   2021.10

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    DOI: 10.26508/lsa.202101049

  • Suv4-20h2 protects against influenza virus infection by suppression of chromatin loop formation. International journal

    Masami Shiimori, Yu Ichida, Ryota Nukiwa, Toshie Sakuma, Haruka Abe, Rei Kajitani, Yuji Fujino, Akira Kikuchi, Takeshi Kawamura, Tatsuhiko Kodama, Shinichi Toyooka, Katsuhiko Shirahige, Gunnar Schotta, Keiji Kuba, Takehiko Itoh, Yumiko Imai

    iScience   24 ( 6 )   102660 - 102660   2021.6

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    DOI: 10.1016/j.isci.2021.102660

  • Clonal hematopoiesis in adult pure red cell aplasia. Reviewed International journal

    Naohito Fujishima, Junki Kohmaru, Souichi Koyota, Keiji Kuba, Tomoo Saga, Ayumi Omokawa, Yuki Moritoki, Shigeharu Ueki, Fumihiro Ishida, Shinji Nakao, Akira Matsuda, Akiko Ohta, Kaoru Tohyama, Hiroshi Yamasaki, Kensuke Usuki, Yasuhiro Nakashima, Shinya Sato, Yasushi Miyazaki, Yasuhito Nannya, Seishi Ogawa, Kenichi Sawada, Kinuko Mitani, Makoto Hirokawa

    Scientific reports   11 ( 1 )   2253 - 2253   2021.1

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    DOI: 10.1038/s41598-021-81890-5

  • Virus database annotations assist in tracing information on patients infected with emerging pathogens. Invited Reviewed International journal

    Nakashima A, Takeya M, Kuba K, Takano M, Nakashima N.

    Informatics in Medicine Unlocked   21   2020.10

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  • Eosinophils promote corneal wound healing via the 12/15‐lipoxygenase pathway

    34 ( 9 )   12492 - 12501   2020.9

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    DOI: 10.1096/fj.202000483r

  • m6A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis

    Yushi Nagaki, Satoru Motoyama, Tomokazu Yamaguchi, Midori Hoshizaki, Yusuke Sato, Teruki Sato, Yukio Koizumi, Akiyuki Wakita, Yuta Kawakita, Kazuhiro Imai, Hiroshi Nanjo, Hiroyuki Watanabe, Yumiko Imai, Yoshihiro Minamiya, Keiji Kuba

    Genes to Cells   25 ( 8 )   547 - 561   2020.8

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  • Essential functions of the CNOT7/8 catalytic subunits of the CCR4-NOT complex in mRNA regulation and cell viability. Reviewed International journal

    Mostafa D, Takahashi A, Yanagiya A, Yamaguchi T, Abe T, Kureha T, Kuba K, Kanegae Y, Furuta Y, Yamamoto T, Suzuki T.

    RNA Biology   17 ( 3 )   403 - 416   2020.3

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    DOI: 10.1080/15476286.2019.1709747.

  • The CCR4-NOT Deadenylase Complex Maintains Adipocyte Identity. Reviewed International journal

    Takahashi A, Takaoka S, Kobori S, Yamaguchi T, Ferwati S, Kuba K, Yamamoto T, Suzuki T

    International journal of molecular sciences   20 ( 21 )   2019.10

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    The CCR4-NOT Deadenylase Complex Maintains Adipocyte Identity.
    Shortening of poly(A) tails triggers mRNA degradation; hence, mRNA deadenylation regulates many biological events. In the present study, we generated mice lacking the Cnot1 gene, which encodes an essential scaffold subunit of the CCR4-NOT deadenylase complex in adipose tissues (Cnot1-AKO mice) and we examined the role of CCR4-NOT in adipocyte function. Cnot1-AKO mice showed reduced masses of white adipose tissue (WAT) and brown adipose tissue (BAT), indicating abnormal organization and function of those tissues. Indeed, Cnot1-AKO mice showed hyperinsulinemia, hyperglycemia, insulin resistance, and glucose intolerance and they could not maintain a normal body temperature during cold exposure. Muscle-like fibrous material appeared in both WAT and BAT of Cnot1-AKO mice, suggesting the acquisition of non-adipose tissue characteristics. Gene expression analysis using RNA-sequencing (RNA-seq) showed that the levels of adipose tissue-related mRNAs, including those of metabolic genes, decreased, whereas the levels of inflammatory response-related mRNAs increased. These data suggest that the CCR4-NOT complex ensures proper adipose tissue function by maintaining adipocyte-specific mRNAs at appropriate levels and by simultaneously suppressing mRNAs that would impair adipocyte function if overexpressed.

    DOI: 10.3390/ijms20215274

  • Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. Reviewed

    EMBO molecular medicine   11 ( 8 )   e9266   2019.8

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    Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy.

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  • Involvement of RSK1 activation in malformin-enhanced cellular fibrinolytic activity Reviewed

    Yukio Koizumi, Kenichiro Nagai, Lina Gao, Souichi Koyota, Tomokazu Yamaguchi, Miyuki Natsui, Yumiko Imai, Keiji Hasumi, Toshihiro Sugiyama, Keiji Kuba

    Scientific Reports   8 ( 1 )   5472   2018.12

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  • The CCR4-NOT complex contributes to repression of Major Histocompatibility Complex class II transcription Reviewed

    Alfonso Rodriguez-Gil, Olesja Ritter, Vera V. Saul, Jochen Wilhelm, Chen-Yuan Yang, Rudolf Grosschedl, Yumiko Imai, Keiji Kuba, Michael Kracht, M. Lienhard Schmitz

    SCIENTIFIC REPORTS   7 ( 1 )   3547   2017.6

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  • Evaluation of Lecithinized Superoxide Dismutase for the Prevention of Acute Respiratory Distress Syndrome in Animal Models Reviewed

    Ken-ichiro Tanaka, Fumiya Tamura, Toshifumi Sugizaki, Masahiro Kawahara, Keiji Kuba, Yumiko Imai, Tohru Mizushima

    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY   56 ( 2 )   179 - 190   2017.2

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    DOI: 10.1165/rcmb.2016-0158OC

  • Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy. Reviewed

    Kimura H, Eguchi S, Sasaki J, Kuba K, Nakanishi H, Takasuga S, Yamazaki M, Goto A, Watanabe H, Itoh H, Imai Y, Suzuki A, Mizushima N, Sasaki T

    JCI insight   2 ( 1 )   e89462   2017.1

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    Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy.

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  • Structure-activity relationship of cyclic pentapeptide malformins as fibrinolysis enhancers Reviewed

    Yukio Koizumi, Kenichiro Nagai, Keiji Hasumi, Keiji Kuba, Toshihiro Sugiyama

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   26 ( 21 )   5267 - 5271   2016.11

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  • Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice Reviewed

    Yang Sun, Feng Guo, Zhen Zou, Chenggang Li, Xiaoxu Hong, Yan Zhao, Chenxuan Wang, Hongliang Wang, Haolin Liu, Peng Yang, Zongsheng Han, Kangtai Liu, Keiji Kuba, Bin Song, Jinming Gao, Ziyao Mo, Dangsheng Li, Bo Li, Qihan Li, Nanshan Zhong, Chen Wang, Josef M. Penninger, Chengyu Jiang

    PARTICLE AND FIBRE TOXICOLOGY   12   4   2015.3

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    DOI: 10.1186/s12989-015-0080-x

  • The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism Reviewed

    Egon Demetz, Andrea Schroll, Kristina Auer, Christiane Heim, Josef R. Patsch, Philipp Eller, Markus Theurl, Igor Theurl, Milan Theurl, Markus Seifert, Daniela Lener, Ursula Stanzl, David Haschka, Malte Asshoff, Stefanie Dichtl, Manfred Nairz, Eva Huber, Martin Stadlinger, Alexander R. Moschen, Xiaorong Li, Petra Pallweber, Hubert Scharnagl, Tatjana Stojakovic, Winfried Maerz, Marcus E. Kleber, Katia Garlaschelli, Patrizia Uboldi, Alberico L. Catapano, Frans Stellaard, Mats Rudling, Keiji Kuba, Yumiko Imai, Makoto Arita, John D. Schuetz, Peter P. Pramstaller, Uwe J. F. Tietge, Michael Trauner, Giuseppe D. Norata, Thierry Claudel, Andrew A. Hicks, Guenter Weiss, Ivan Tancevski

    CELL METABOLISM   20 ( 5 )   787 - 798   2014.11

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  • Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations Reviewed

    Takuro Arimura, Kenji Onoue, Yumiko Takahashi-Tanaka, Taisuke Ishikawa, Masayoshi Kuwahara, Mitsutoshi Setou, Shuji Shigenobu, Katsushi Yamaguchi, Anne T. Bertrand, Noboru Machida, Kazumi Takayama, Masayuki Fukusato, Ryo Tanaka, Satoshi Somekawa, Tomoya Nakano, Yoshihisa Yamane, Keiji Kuba, Yumiko Imai, Yoshihiko Saito, Gisele Bonne, Akinori Kimura

    CARDIOVASCULAR RESEARCH   99 ( 3 )   382 - 394   2013.8

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  • Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases Reviewed

    Keiji Kuba, Yumiko Imai, Josef M. Penninger

    CIRCULATION JOURNAL   77 ( 2 )   301 - 308   2013.2

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    DOI: 10.1253/circj.CJ-12-1544

  • ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation Reviewed

    Tatsuo Hashimoto, Thomas Perlot, Ateequr Rehman, Jean Trichereau, Hiroaki Ishiguro, Magdalena Paolino, Verena Sigl, Toshikatsu Hanada, Reiko Hanada, Simone Lipinski, Birgit Wild, Simone M. R. Camargo, Dustin Singer, Andreas Richter, Keiji Kuba, Akiyoshi Fukamizu, Stefan Schreiber, Hans Clevers, Francois Verrey, Philip Rosenstiel, Josef M. Penninger

    NATURE   487 ( 7408 )   477 - U89   2012.7

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    DOI: 10.1038/nature11228

  • Apelin Treatment Increases Complete Fatty Acid Oxidation, Mitochondrial Oxidative Capacity, and Biogenesis in Muscle of Insulin-Resistant Mice Reviewed

    Camille Attane, Camille Foussal, Sophie Le Gonidec, Alexandre Benani, Daniele Daviaud, Estelle Wanecq, Rocio Guzman-Ruiz, Cedric Dray, Veronic Bezaire, Chloe Rancoule, Keiji Kuba, Mariano Ruiz-Gayo, Thierry Levade, Josef Penninger, Remy Burcelin, Luc Penicaud, Philippe Valet, Isabelle Castan-Laurell

    DIABETES   61 ( 2 )   310 - 320   2012.2

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  • Trilogy of ACE2: A peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters Reviewed

    Keiji Kuba, Yumiko Imai, Takayo Ohto-Nakanishi, Josef M. Penninger

    PHARMACOLOGY & THERAPEUTICS   128 ( 1 )   119 - 128   2010.10

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  • Losartan inhibits LPS-induced inflammatory signaling through a PPAR gamma-dependent mechanism in human THP-1 macrophages Reviewed

    Jianbo An, Toshiaki Nakajima, Keiji Kuba, Akinori Kimura

    HYPERTENSION RESEARCH   33 ( 8 )   831 - 835   2010.8

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  • Angiotensin-Converting Enzyme 2 (ACE2) in Disease Pathogenesis Reviewed

    Yumiko Imai, Keiji Kuba, Takayo Ohto-Nakanishi, Josef M. Penninger

    CIRCULATION JOURNAL   74 ( 3 )   405 - 410   2010.3

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  • PI3K gamma Protects from Myocardial Ischemia and Reperfusion Injury through a Kinase-Independent Pathway Reviewed

    Bernhard J. Haubner, G. Gregory Neely, Jakob G. J. Voelkl, Federico Damilano, Keiji Kuba, Yumiko Imai, Vukoslav Komnenovic, Agnes Mayr, Otmar Pachinger, Emilio Hirsch, Josef M. Penninger, Bernhard Metzler

    PLOS ONE   5 ( 2 )   e9350   2010.2

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  • Inhibition of Endostatin/Collagen XVIII Deteriorates Left Ventricular Remodeling and Heart Failure in Rat Myocardial Infarction Model Reviewed

    Kazuya Isobe, Keiji Kuba, Yasuhiro Maejima, Jun-ichi Suzuki, Shunichiro Kubota, Mitsuaki Isobe

    CIRCULATION JOURNAL   74 ( 1 )   109 - 119   2010.1

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  • Orphan Transporter SLC6A18 Is Renal Neutral Amino Acid Transporter B(0)AT3 Reviewed

    Dustin Singer, Simone M. R. Camargo, Katja Huggel, Elisa Romeo, Ursula Danilczyk, Keiji Kuba, Serge Chesnov, Marc G. Caron, Josef M. Penninger, Francois Verrey

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 30 )   19953 - 19960   2009.7

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    DOI: 10.1074/jbc.M109.011171

  • Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models Reviewed

    Yuko Kishi, Keiji Kuba, Takahiro Nakamura, Jinhua Wen, Yoshinori Suzuki, Shinya Mizuno, Toshihiro Nukiwa, Kunio Matsumoto, Toshikazu Nakamura

    CANCER SCIENCE   100 ( 7 )   1351 - 1358   2009.7

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  • The role of ACE2 in pulmonary diseases - relevance for the nephrologist Reviewed

    Gavin Y. Oudit, Yumiko Imai, Keiji Kuba, James W. Scholey, Josef M. Penninger

    NEPHROLOGY DIALYSIS TRANSPLANTATION   24 ( 5 )   1362 - 1365   2009.5

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    DOI: 10.1093/ndt/gfp065

  • Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations Reviewed

    Simone M. R. Camargo, Dustin Singer, Victoria Makrides, Katja Huggel, Klaas M. Pos, Carsten A. Wagner, Keiji Kuba, Ursula Danilczyk, Flemming Skovby, Robert Kleta, Josef M. Penninger, Francois Verrey

    GASTROENTEROLOGY   136 ( 3 )   872 - 882   2009.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1053/j.gastro.2008.10.055

  • The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice Reviewed

    Yumiko Imai, Keiji Kuba, Josef M. Penninger

    EXPERIMENTAL PHYSIOLOGY   93 ( 5 )   543 - 548   2008.5

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    Language:English  

    DOI: 10.1113/expphysiol.2007.040048

  • [Lessons from SARS: a new potential therapy for acute respiratory distress syndrome (ARDS) with angiotensin converting enzyme 2 (ACE2)]. Reviewed

    Imai Y, Kuba K, Penninger JM

    Masui. The Japanese journal of anesthesiology   57 ( 3 )   302 - 310   2008.3

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    Language:Japanese  

    [Lessons from SARS: a new potential therapy for acute respiratory distress syndrome (ARDS) with angiotensin converting enzyme 2 (ACE2)].

  • Endogenous apelin maintains heart contractility in aging and pressure overload Reviewed

    Kuba Keiji, Zhang Liyong, Imai Yumiko, Chen Manyin, Maekawa Yuichiro, Leschnik Michael, Arab Sara, Beetz Nadine, Hein Lutz, Kimura Akinori, Liu Peter P, Perminger Josef M

    CIRCULATION   116 ( 16 )   248   2007.10

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    Endogenous apelin maintains heart contractility in aging and pressure overload

  • Lessons from SARS: control of acute lung failure by the SARS receptor ACE2 Reviewed

    Keiji Kuba, Yumiko Imai, Shuan Rao, Chengyu Jiang, Josef M. Penninger

    JOURNAL OF MOLECULAR MEDICINE-JMM   84 ( 10 )   814 - 820   2006.10

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    Language:English  

    DOI: 10.1007/s00109-006-0094-9

  • Angiotensin-converting enzyme 2 in lung diseases Reviewed

    K Kuba, Y Imai, JM Penninger

    CURRENT OPINION IN PHARMACOLOGY   6 ( 3 )   271 - 276   2006.6

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    Language:English  

    DOI: 10.1016/j.coph.2006.03.001

  • HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model. Reviewed

    Nakabayashi M, Morishita R, Nakagami H, Kuba K, Matsumoto K, Nakamura T, Tano Y, Kaneda Y, Diabetologia, v

    46 ( 1 )   115 - 123   2003.1

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    HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model.
    Nakabayashi M, Morishita R, Nakagami H, Kuba K, Matsumoto K, Nakamura T, Tano Y, Kaneda Y, Diabetologia, 2003, vol. 46, no. 1, pp. 115-123, 2003

  • Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor Reviewed

    Kazuhiko Date, Kunio Matsumoto, Keiji Kuba, Hideo Shimura, Masao Tanaka, Toshikazu Nakamura

    Oncogene   17 ( 23 )   3045 - 3054   1998.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/sj.onc.1202231

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Presentations

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MISC

  • CAG-hACE2 Tgマウスを用いたSARS-CoV-2経気道感染モデルの樹立

    内海 大知, 浅賀 正充, 鎌田 春彦, 永田 諭志, 仲地 ゆたか, 山口 智和, 河岡 義裕, 久場 敬司, 保富 康宏

    日本薬学会年会要旨集   2022.3

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    Language:Japanese  

  • 【循環器疾患におけるレニン・アンジオテンシン・アルドステロン(RAA)系の新たな展望】ACE2の循環器疾患および感染症における意義

    久場 敬司

    Cardiac Practice   32 ( 2 )   116 - 121   2022.2   ISSN:0915-874X

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    Language:Japanese   Publisher:(株)メディカルレビュー社  

  • Establishment of SARS-CoV-2 respiratory tract infection model in CAG promoter-driven hACE2 transgenic mice

    Utsumi Daichi, Masamitsu Asaka, Haruhiko Kamada, Satoshi Nagata, Yutaka Nakachi, Tomokazu Yamaguchi, Yoshihiro Kawaoka, Keiji Kuba, Yasuhiro Yasutomi

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   95   2 - P   2022   eISSN:2435-4953

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    Publisher:Japanese Pharmacological Society  

    DOI: 10.1254/jpssuppl.95.0_2-p-173

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  • 環状ペプチドマルホルミンが賦活化する細胞性血栓溶解にはRSK1の活性化が関与する

    小泉幸央, 長井賢一郎, GAO Lina, 山口智和, 夏井美幸, 今井由美子, 蓮見惠司, 杉山俊博, 久場敬司

    日本農芸化学会大会講演要旨集(Web)   2018.3

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    Language:Japanese  

  • Analysis for the role of CCR4-NOT complex in regulation of adenine nucleotide metabolism in the hearts

    Tomokazu Yamaguchi, Takashi Suzuki, Teruki Sato, Miyuki Natsui, Ayumi Kadowaki, Chitose Sato, Yukio Koizumi, Akinori Takahashi, Tadashi Yamamoto, Yumiko Imai, Keiji Kuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   2016.3

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    Language:English  

  • 脂質シグナリングとその破綻がもたらす病態の理解 心肥大におけるホスホイノシタイド代謝酵素Vps34のタンパク質分解機構の役割

    木村 洋貴, 江口 賢史, 久場 敬司, 今井 由美子, 高須賀 俊輔, 伊藤 玲悦, 中村 亮太郎, 中西 広樹, 石川 将己, 佐々木 純子, 山崎 正和, 佐々木 雄彦

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   2015.12

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    Language:Japanese  

  • Dissecting the role of CCR4-NOT-associated ubiquitin converting enzyme in controlling heart functions

    Tomokazu Yamaguchi, Ayumi Kadowaki, Yukio Koizumi, Miyuki Natsui, Chitose Satou, Yumiko Imai, Keiji Kuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   2015.7

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    Language:English  

  • A crucial role of CNOT3 in stem cell proliferation and early embryonic development

    Yukio Koizumi, Tomokazu Yamaguchi, Ayumi Kadowaki, Miyuki Natsui, Chitose Sato, Yumiko Imai, Keiji Kuba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   2015.7

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    Language:English  

  • Angiotensin-Converting-Enzyme 2 (rhACE2) Potently Attenuates the Negative Hemodynamic Effects of Angiotensin II (ATII) and Improves Post-Myocardial Infarction (MI) Remodeling

    Bernhard Unsoeld, Manfred Schuster, Hans Loibner, Alexander Becker, Tim Seidler, Claudius Jacobshagen, Keiji Kuba, Yumiko Imai, Josef Penninger, Gerd Hasenfuss

    CIRCULATION   2008.10

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  • The absence of PI3K gamma is beneficial in a mouse model of myocardial ischemia/reperfusion

    Bernhard J. Haubner, Julia Schwighofer, Florian Huber, Greg Neely, Keiji Kuba, Elisabetta Conci, Markus C. Stuehlinger, Hannes Alber, Otmar Pachinger, Josef Penninger, Bernhard Metzler

    CIRCULATION   2007.10

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  • Angiotensin-converting enzyme 2 in acute respiratory distress syndrome

    Y. Imai, K. Kuba, J. M. Penninger

    CELLULAR AND MOLECULAR LIFE SCIENCES   2007.8

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    Language:English  

    DOI: 10.1007/s00018-007-6228-6

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Industrial property rights

Patent   Number of applications: 1   Number of registrations: 0
Utility model   Number of applications: 0   Number of registrations: 0
Design   Number of applications: 0   Number of registrations: 0
Trademark   Number of applications: 0   Number of registrations: 0

Professional Memberships

  • 日本薬理学会

  • 日本生化学会

  • 日本分子生物学会

  • 日本循環薬理学会

  • 日本癌学会

Committee Memberships

  • Councilor  

    2023.8   

  • Councilor  

    2023.8   

Academic Activities

  • シンポジウム座長

    第33回日本循環薬理学会 シンポジウム  ( 大阪医科薬科大学 ) 2024.1

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    Type:Competition, symposium, etc. 

  • シンポジウム座長、特別講演座長、ランチョンセミナー座長

    第97回日本薬理学会  ( 神戸市 ) 2023.12

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    Type:Competition, symposium, etc. 

  • 当番世話人

    第10回CCR4-NOT研究会  ( 福岡市 ) 2023.11

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    Type:Competition, symposium, etc. 

  • シンポジウム座長

    第96回日本生化学会大会  ( 福岡市 ) 2023.10 - 2023.11

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    Type:Competition, symposium, etc. 

  • 提案代表者

    生理研心血管研究会-炎症・免疫系と心血管系の相互作用から切り拓く 循環生理機能の解析-  ( 生理学研究所 ) 2023.10

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    Type:Competition, symposium, etc. 

  • 部会長

    第74回日本薬理学会北部会  ( 秋田市 ) 2023.9

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    Type:Competition, symposium, etc. 

  • Frontis in Immunology

    2023.8

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    Type:Academic society, research group, etc. 

  • Journal of Biochemistry International contribution

    2023.8

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    Type:Academic society, research group, etc. 

  • Screening of academic papers

    Role(s): Peer review

    2023

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:7

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Research Projects

  • 免疫体質を規定するRNA代謝ネットワークの解析

    Grant number:24K02256  2024.4 - 2027.3

    科学研究費助成事業  基盤研究(B)

    海老原 敬, 久場 敬司, 立松 恵, 高須賀 俊輔

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    Grant type:Scientific research funding

    免疫には一定の方向性とそれを司る転写因子が存在する。ウイルス感染細胞や腫瘍細胞の除去を目的としたT-bet依存性の1型免疫、抗寄生虫免疫やアレルギー炎症を誘導するGATA-3依存性の2型免疫、細胞に入り込まない病原体(細菌や真菌)に対するRorgt依存性の3型免疫、炎症の抑制を目的としたFoxp3依存性の制御性免疫である。それぞれの免疫型の強弱は、免疫体質として現れる。例えば、1型免疫が弱い傾向にあるとウイルス感染に弱い体質をもつことになる。本研究では、これら免疫体質を制御する転写因子群のmRNA代謝機構を網羅的に解析し、免疫体質を司るmRNA代謝ネットワークの全貌を明らかにする。

    CiNii Research

  • Elucidation of RNA-guided molecular networks in response to heart failure stress

    Grant number:24K02215  2024 - 2026

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

    CiNii Research

  • 癌の転移・再発における細胞外Galectin-Xを介した免疫抑制機構の解明

    2023

    日本学術振興会  科学研究費助成事業  基盤研究(C)

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

  • 武田研究助成ハイリスク感染症

    2023

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    Grant type:Donation

  • 高転移腫瘍の空間的トランスクリプトーム解析による癌転移の新しい予測・治療法の開発

    2022 - 2023

    日本学術振興会  科学研究費助成事業  挑戦的研究(萌芽)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 自然リンパ球特異的mRNA代謝による病態制御機構の解明

    2021 - 2023

    日本学術振興会  科学研究費助成事業  基盤研究(B)

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

  • 重症ウイルス感染症における高次エピゲノム作動原理の解明と新規治療基盤の確立

    Grant number:17H06179 

    今井 由美子, 久場 敬司

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    Grant type:Scientific research funding

    インフルエンザウイルスや新型コロナウイルス等のウイルス感染に伴う宿主高次エピゲノムの作動原理について研究した。特にH4K20のトリメチル化酵素であるSuv4-20h2は非感染状態ではコヒーシンと結合してヘテロクロマチンの安定化に関わっているが、インフルエンザウイルス感染に伴ってコヒーシンの結合が低下して、コヒーシンは特定のゲノム領域の境界にローディングして、クロマチンループが形成され、感染病態に関わる領域の遺伝子発現が活性化することを見出した。さらにCOVID-19患者検体を用いて、クロマチンの構造変化をゲノムワイドに解析し、重症度との関連性を示唆する知見を得た。

    CiNii Research

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Class subject

  • 医薬品・医療機器開発と治験

    2024.6 - 2024.8   Summer quarter

  • 臨床研究の倫理と規制

    2024.4 - 2024.6   Spring quarter

  • 医薬品・医療機器開発と治験

    2023.10 - 2024.3   Second semester

  • 薬理学総論

    2023.4 - 2023.9   First semester

  • 薬理学各論

    2023.4 - 2023.9   First semester

  • 研究室配属I

    2023.4 - 2023.9   First semester

  • 臨床研究の倫理と規制

    2023.4 - 2023.9   First semester

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FD Participation

  • 2024.3   Role:Participation   Title:医学部・医学系学府合同教育FD 大学病院の苦悩と医学研究の課題

    Organizer:[Undergraduate school/graduate school/graduate faculty]

Visiting, concurrent, or part-time lecturers at other universities, institutions, etc.

  • 2023  秋田大学医学部 

Social Activities

  • 令和5年度 福岡県生物部会二学期研修会

    福岡県高等学校生物部会  福岡市  2023.12

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Seminar, workshop