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SAWADA Takahiro
Engineering Biology Research Center
Assistant Professor

Researcher basic information

■ Research Keyword
  • 神経幹細胞
  • 細胞内情報伝達
  • Eph
  • マーモセット
  • 体格
  • ephrin(エフリン)
  • 再生医療
  • EphA4
  • ラット
  • 成長障害
  • IGF1
  • ephrin
  • 成長ホルモン
  • パーキンソン病
  • 細胞分化
  • 細胞骨格・運動
  • 細胞構造・機能
  • 細胞情報伝達機構
■ Research Areas
  • Life sciences / Neuroscience - general
  • Life sciences / Metabolism and endocrinology
  • Life sciences / Cell biology
  • Life sciences / Molecular biology
  • Life sciences / Functional biochemistry

Research activity information

■ Award
  • Mar. 2014 和歌山県立医科大学, 和歌山県立医科大学若手研究奨励賞
    澤田 貴宏

  • 2011 和歌山県立医科大学, 2011 Wakayama Medical Award for Young Researchers
    Takahiro Sawada

■ Paper
  • Qingfa Chen, Jia Liu, Takahiro Sawada, Chuanfei Wei, Shichao Wu, Fabin Han
    Mar. 2020, EXPERIMENTAL AND THERAPEUTIC MEDICINE, 19(3) (3), 1789 - 1796, English
    Scientific journal

  • Koji Haratani, Hidetoshi Hayashi, Takayuki Takahama, Yasushi Nakamura, Shuta Tomida, Takeshi Yoshida, Yasutaka Chiba, Takahiro Sawada, Kazuko Sakai, Yoshihiko Fujita, Yosuke Togashi, Junko Tanizaki, Hisato Kawakami, Akihiko Ito, Kazuto Nishio, Kazuhiko Nakagawa
    Sep. 2019, JOURNAL FOR IMMUNOTHERAPY OF CANCER, 7(1) (1), English
    [Refereed]
    Scientific journal

  • Nobuyuki Bandoh, Toshiaki Akahane, Takashi Goto, Michihisa Kono, Haruyuki Ichikawa, Takahiro Sawada, Tomomi Yamaguchi, Hiroshi Nakano, Yumiko Kawase, Yasutaka Kato, Hajime Kamada, Yasuaki Harabuchi, Kazuo Shimizu, Hiroshi Nishihara
    Dec. 2018, Oncology letters, 16(6) (6), 7278 - 7286, English, International magazine
    [Refereed]
    Scientific journal

  • Takahiro Sawada, Daiki Arai, Xuefeng Jing, Masayasu Miyajima, Stuart J. Frank, Kazushige Sakaguchi
    Jul. 2017, PLOS ONE, 12(7) (7), e0180785, English, International magazine
    [Refereed]
    Scientific journal

  • Yoshinobu Takahashi, Takahiro Sawada, Toshiaki Akahane, Yumiko Kawase, Hidetoshi Ikeda, Keishi Makino, Hideo Nakamura, Takuichiro Hide, Shigetoshi Yano, Naoya Hashimoto, Hajime Kamada
    Jul. 2017, ONCOLOGY LETTERS, 14(1) (1), 264 - 270, English
    [Refereed]
    Scientific journal

  • Qingfa Chen, Takahiro Sawada, Kazushige Sakaguchi, Fabin Han
    2017, JOURNAL OF NEURORESTORATOLOGY, 5, 133 - 141, English
    Scientific journal

  • Jing Xuefeng, Takashi Sonoki, Masayasu Miyajima, Takahiro Sawada, Nanako Terada, Shigeki Takemura, Kazushige Sakaguchi
    Jun. 2016, CANCER MEDICINE, 5(6) (6), 1214 - 1227, English
    [Refereed]
    Scientific journal

  • Takahiro Sawada, Daiki Arai, Xuefeng Jing, Kenryo Furushima, Qingfa Chen, Kazuki Kawakami, Hideyuki Yokote, Masayasu Miyajima, Kazushige Sakaguchi
    May 2015, PLOS ONE, 10(5) (5), e0128826, English
    [Refereed]
    Scientific journal

  • Qingfa Chen, Daiki Arai, Kazuki Kawakami, Takahiro Sawada, Xuefeng Jing, Masayasu Miyajima, Syu-ichi Hirai, Kazushige Sakaguchi, Kenryo Furushima
    May 2015, PLOS ONE, 10(5) (5), e0126942, English
    [Refereed]
    Scientific journal

  • Yoshinobu Takahashi, Toshiaki Akahane, Takahiro Sawada, Hidetoshi Ikeda, Akira Tempaku, Shigeru Yamauchi, Hiroshi Nishihara, Shinya Tanaka, Kazumi Nitta, Wataru Ide, Ikuo Hashimoto, Hajime Kamada
    Mar. 2015, WORLD JOURNAL OF SURGICAL ONCOLOGY, 13, 100, English
    [Refereed]
    Scientific journal

  • Xuefeng Jing, Masayasu Miyajima, Takahiro Sawada, Qingfa Chen, Keiji Iida, Kenryo Furushima, Daiki Arai, Kazuo Chihara, Kazushige Sakaguchi
    Sep. 2012, CELL REPORTS, 2(3) (3), 652 - 665, English, International magazine
    [Refereed]
    Scientific journal

  • Xuefeng Jing, Hideto Miwa, Takahiro Sawada, Ichiro Nakanishi, Tomoyoshi Kondo, Masayasu Miyajima, Kazushige Sakaguchi
    Feb. 2012, PLOS ONE, 7(2) (2), e32019, English
    [Refereed]
    Scientific journal

  • Masayuki Kawahara, Yasumasa Iwasaki, Kazushige Sakaguchi, Takafumi Taguchi, Mitsuru Nishiyama, Takeshi Nigawara, Machiko Kambayashi, Takahiro Sawada, Xuefeng Jing, Masayasu Miyajima, Yoshio Terada, Kozo Hashimoto, Toshihoro Suda
    Sep. 2010, BONE, 47(3) (3), 534 - 541, English
    [Refereed]
    Scientific journal

  • Takahiro Sawada, Xuefeng Jing, Yueqiang Zhang, Emi Shimada, Hideyuki Yokote, Masayasu Miyajima, Kazushige Sakaguchi
    Mar. 2010, GENES TO CELLS, 15(3) (3), 297 - 311, English
    [Refereed]
    Scientific journal

  • Yueqiang Zhang, Takahiro Sawada, Xuefeng Jing, Hideyuki Yokote, Xiaomei Yan, Kazushige Sakaguchi
    Oct. 2007, JOURNAL OF BIOLOGICAL CHEMISTRY, 282(42) (42), 31103 - 31112, English
    [Refereed]
    Scientific journal

  • Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains.
    Hideyuki Yokote, Koji Fujita, Xuefeng Jing, Takahiro Sawada, Sitai Liang, Li Yao, Xiaomei Yan, Yueqiang Zhang, Joseph Schlessinger, Kazushige Sakaguchi
    A yeast two-hybrid analysis has shown that the juxtamembrane region of FGF receptor 3 (FGFR3) interacts with the cytoplasmic domain of EphA4, which is a member of the largest family of receptor tyrosine kinases. Complex formation between the two receptors was shown to be mediated by direct interactions between the juxtamembrane domain of FGFR1, FGFR2, FGFR3, or FGFR4 and the N-terminal portion of the tyrosine kinase domain of EphA4. Activation of FGFR1 in transfected cells resulted in tyrosine phosphorylation of a kinase-negative EphA4 mutant and activation of EphA4 led to tyrosine phosphorylation of a kinase-negative FGFR1 mutant. Moreover, both receptors stimulate tyrosine phosphorylation of the docking protein FRS2alpha and induce mitogen-activated protein kinase stimulation with a time course and intensity that depends on the ligand that is applied. We also demonstrate that FGF-receptor-mediated mitogen-activated protein kinase stimulation is potentiated in cells costimulated with ephrin-A1. The direct interaction between EphA4 and FGFRs and the potentiation of FGF response that is induced by ephrin-A1 stimulation may modulate the biological responses that are mediated by these receptor families in cells or tissues in which the two receptors are coexpressed.
    Dec. 2005, Proceedings of the National Academy of Sciences of the United States of America, 102(52) (52), 18866 - 71, English, International magazine
    [Refereed]
    Scientific journal

  • Nuclear localization of glyceraldehyde-3-phosphate dehydrogenase is not involved in the initiation of apoptosis induced by 1-Methyl-4-phenyl-pyridium iodide (MPP+).
    Rieko Kodama, Tomoyoshi Kondo, Hideyuki Yokote, Xuefeng Jing, Takahiro Sawada, Masaya Hironishi, Kazushige Sakaguchi
    Nuclear localization of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is implicated in the process of apoptosis. To study the function of GAPDH, we expressed GAPDH C-terminally fused with or without nuclear localization signal (NLS) in SH-SY5Y and NB41A3 cells using a retrovirus expression system. GAPDH carrying NLS (GAPDH-NLS) was expressed mainly in the nucleus. However, expression of GAPDH-NLS did not cause any difference in cell survival rate as compared to that of the vector alone or GAPDH without NLS. Treatment with 1-Methyl-4-phenyl-pyridium iodide (MPP+) caused no difference in the cell survival rate or in the pattern or extent of apoptosis among the three transductants. In the cells expressing GAPDH without NLS, MPP+ did not cause visible translocation of GAPDH into nucleus before the onset of apoptosis. Since GAPDH is known to comprise a CRM1-mediated nuclear export signal, we blocked the nuclear export of GAPDH by treatment with leptomycin B, an inhibitor of CRM1-mediated nuclear export. The treatment did not cause any difference in apoptosis among the three transductants. An additional treatment with MPP+ induced no apoptotic difference in these cells. Thus, we have concluded that a simple nuclear localization of GAPDH does not induce apoptosis, and that MPP+-induced apoptosis is not caused by nuclear translocation of GAPDH.
    Dec. 2005, Genes to cells : devoted to molecular & cellular mechanisms, 10(12) (12), 1211 - 9, English, International magazine
    [Refereed]
    Scientific journal

  • Fibroblast growth factor 23 reduces expression of type IIa Na+/Pi co-transporter by signaling through a receptor functionally distinct from the known FGFRs in opossum kidney cells.
    Xiaomei Yan, Hideyuki Yokote, Xuefeng Jing, Li Yao, Takahiro Sawada, Yueqiang Zhang, Sitai Liang, Kazushige Sakaguchi
    Fibroblast growth factor (FGF) 23 is an important phosphaturic factor that inhibits inorganic phosphate (Pi) reabsorption from the renal proximal tubule. Its overproduction and proteolysis-resistant mutation such as R179Q cause tumor-induced osteomalacia and autosomal dominant hypophosphatemic rickets, respectively. To clarify the signaling mechanisms of FGF23 that mediate the reduction of Pi reabsorption, we inhibited the function of the known FGFRs in opossum kidney (OK-E) cells by expressing a dominant-negative (DN) form of FGFR. OK-E cells, which represent the renal proximal tubular cells, expressed all four known FGFRs. FGF23(R179Q) bound to and activated FGFR2, a prominent FGFR expressed in OK-E cells. The activated receptor transmitted a signal to increase the expression of type IIa Na(+)/Pi co-transporter and the Pi uptake. Expression of FGFR2(DN), which suppresses the major FGFR-mediated signal through the FRS2alpha-ERK pathway, reversed the function of FGF23(R179Q). When FGF23(R179Q) was applied to the basolateral side of polarized OK-E cells, regardless of the FGFR2(DN) expression, the apical Pi uptake decreased significantly. The apical application of FGF23(R179Q) in the polarized cells did not show such decrease but increase. The exogenously expressed FGFR2 was detectable only at the apical membrane. These results suggest that an FGF23 receptor, which is functionally distinct from the known FGFRs, is expressed at the basolateral membrane of OK-E cells.
    May 2005, Genes to cells : devoted to molecular & cellular mechanisms, 10(5) (5), 489 - 502, English, International magazine
    [Refereed]
    Scientific journal

■ MISC
  • Usefulness of establishing a genome center specialized for lung cancer
    白石直樹, 木村竜一朗, 森樹史, 澤田貴宏, 清水重喜, 坂井和子, 西尾和人, 伊藤彰彦
    2021, 医学検査, 70(3) (3)

  • 腸内細菌叢と腸管炎症・がん化のインタラクションに関する検討
    澤田貴宏, 中村有貴, 高濱隆幸, 坂井和子, 横山省三, 山上裕機, 西尾和人
    2018, 日本がん分子標的治療学会学術集会プログラム・抄録集, 22nd

  • 原発不明がんにおける腫瘍微小免疫環境と予後の関連性
    原谷浩司, 林秀敏, 高濱隆幸, 澤田貴宏, 中村靖司, 伊藤彰彦, 千葉康敬, 谷崎潤子, 藤田至彦, 坂井和子, 西尾和人, 中川和彦
    2018, 日本臨床腫瘍学会学術集会(CD-ROM), 16th

  • がん遺伝子診断外来を始めて 当院におけるTriple negative breast cancer ERBB2遺伝子変異の報告
    赤羽 俊章, 澤田 貴宏, 河瀬 ゆみこ, 川見 弘之, 中島 恵, 難波 清, 原田 大, 西原 広史
    (一社)日本乳癌学会, Jul. 2017, 日本乳癌学会総会プログラム抄録集, 25回, 292 - 292, Japanese

  • 乳腺生検検体を使用した迅速病理診断とNext generation sequencerを使用した個別化医療への試み
    赤羽 俊章, 澤田 貴宏, 難波 清, 川見 弘之, 中島 恵, 原田 大, 西原 広史
    (NPO)日本乳癌検診学会, Oct. 2016, 日本乳癌検診学会誌, 25(3) (3), 397 - 397, Japanese

  • 浸潤性乳管癌HER2(2+)症例のカスタム遺伝子パネルを使用した次世代シークエンサー解析
    赤羽 俊章, 澤田 貴宏, 川見 弘之, 難波 清, 原田 大, 西原 広史
    日本癌学会, Oct. 2016, 日本癌学会総会記事, 75回, P - 2159, English

  • 浸潤性乳管癌HER2(2+)症例の次世代シークエンサー(NGS)解析
    赤羽俊章, 澤田貴宏, 川見弘之, 中島恵, 難波清, 西原広史
    2016, 日本乳癌学会学術総会プログラム・抄録集, 24th

  • Eph-FGFR-FRS2α複合体シグナルがマウス胎生神経幹細胞の増殖と分化を調節する
    澤田 貴宏, 新井 大貴, 京 雪楓, 古島 謙亮, 陳 清法, 河上 和紀, 横手 秀行, 宮嶋 正康, 鎌田 一, 坂口 和成
    (公社)日本生化学会, Dec. 2015, 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, 88回・38回, [1P0206] - [1P0206], English

  • 乳癌の進行における体液性および細胞-細胞接触媒介シグナルによるホストEphA4の調節
    京 雪楓, 園木 孝志, 宮嶋 正康, 新井 大貴, 澤田 貴宏, 寺田 菜々子, 竹村 重輝, 坂口 和成
    (公社)日本生化学会, Dec. 2015, 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, 88回・38回, [1P1059] - [1P1059], English

  • Xuefeng Jing, Takashi Sonoki, Masayasu Miyajima, Takahiro Sawada, Nanako Terada, Kenryo Furushima, Daiki Arai, Kazuki Kawakami, Kazushige Sakaguchi
    May 2015, CANCER RESEARCH, 75, English
    Summary international conference

  • BRAF V600E変異のあるadult glioblastoma with classical histologic featuresの1例
    高橋義信, 池田英敏, 赤羽俊章, 澤田貴宏, 西原広史, 田中伸哉, 新田一美, 井出渉, 橋本郁郎, 鎌田一
    日本脳腫瘍病理学会, 2015, Brain Tumor Pathology. Supplement, 32(Suppl.) (Suppl.), 132 - 132, Japanese

  • 体格形成に関与するGHシグナル定説への挑戦
    澤田貴宏
    上原記念生命科学財団, 05 Dec. 2014, 上原記念生命科学財団研究報告集(CD-ROM), 28, ROMBUNNO.135 - 4, Japanese

  • A NOVEL IGF1 SIGNALLING PATHWAY REGULATED BY EPHA4 DELAYS CANCER DEVELOPMENT INDUCED BY 4T1 MURINE BREAST CANCER ISOGRAFTS
    Xuefeng Jing, Takashi Sonoki, Masayasu Miyajima, Takahiro Sawada, Kenryo Furushima, Nanako Terada, Daiki Arai, Kazuki Kawakami, Kazushige Sakaguchi
    Dec. 2014, ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, 10, 208 - 209, English
    Summary international conference

  • 甲状腺乳頭癌の次世代シークエンサー(NGS)による解析
    赤羽俊章, 坂東伸幸, 後藤孝, 大貫なつみ, 山口朋美, 澤田貴宏, 福島祐介, 佐和弘基, 西原広史
    30 Sep. 2014, 日本病理学会会誌, 103(2) (2), 51, Japanese

  • 新規体格形成シグナル伝達系における分子機構の解析
    新井大貴, 澤田貴宏, 京雪楓, 古島謙亮, 河上和紀, 陳清法, 宮島正康, 坂口和成
    (一社)日本内分泌学会, 01 Apr. 2014, 日本内分泌学会雑誌, 90(1) (1), 252 - 252, Japanese

  • EphA4/GH受容体ヘテロ複合体を介するIGF1産生シグナル制御メカニズムの解析(第二報)
    新井大貴, 澤田貴宏, 京雪楓, 古島謙亮, 河上和紀, 宮嶋正康, 坂口和成
    2014, 日本分子生物学会年会プログラム・要旨集(Web), 37th

  • 中枢神経原発悪性リンパ腫のMCP‐1発現:全身性瀰漫性大細胞性B細胞リンパ腫と比較して
    高橋義信, 澤田貴宏, 赤羽俊章, 天白昌, 池田英敏, 野老山博紀, 前田大介, 坪田誠之, 古川博規, 山内滋, 新田一美, 西尾明正, 佐和弘基, 井出渉, 橋本郁郎, 鎌田一
    2014, 日本脳腫瘍学会プログラム・抄録集, 32nd, 194, Japanese

  • 次世代シークエンサーを用いた髄膜腫の遺伝子変異解析
    池田英敏, 高橋義信, 天白晶, 赤羽俊章, 澤田貴宏, 野老山博紀, 前田大介, 坪田誠之, 古川博規, 山内滋, 佐和弘基, 西尾明正, 橋本郁郎, 新田一美, 井出渉, 鎌田一
    2014, 日本脳腫瘍学会プログラム・抄録集, 32nd, 183, Japanese

  • 体格形成に関与するGHシグナル定説への挑戦
    澤田 貴宏
    上原記念生命科学財団, 2014, 上原記念生命科学財団研究報告集, 28, 1 - 4, Japanese

  • 成長ホルモン(GH)‐インスリン様成長因子1(IGF1)軸(GH‐IGF1 axis)シグナル伝達系の新展開
    坂口和成, 澤田貴宏, 新井大貴, 京雪楓, 古島謙亮, 河上和紀, 宮嶋正康
    (一社)日本内分泌学会, 20 Sep. 2013, 日本内分泌学会雑誌, 89(2) (2), 446 - 446, Japanese

  • 体格決定の新規分子機構
    坂口和成, 澤田貴宏, 京雪楓, 新井大貴, 古島謙亮, 飯田啓二, 千原和夫, 宮嶋正康
    (一社)日本内分泌学会, 01 Apr. 2013, 日本内分泌学会雑誌, 89(1) (1), 159 - 159, Japanese

  • EphA4/GH受容体ヘテロ複合体を介するIGF1産生シグナル制御メカニズムの解析
    新井大貴, 澤田貴宏, 京雪楓, 古島謙亮, 坂口和成
    2013, 日本分子生物学会年会プログラム・要旨集(Web), 36th, WEB ONLY 3P-0470, Japanese

  • 大脳皮質の神経細胞発生過程におけるEphA4の機能解析
    古島謙亮, CHEN Qingfa, 新井大貴, 澤田貴宏, 河上和紀, 宮嶋正康, 平井秀一, 坂口和成
    2013, 日本分子生物学会年会プログラム・要旨集(Web), 36th, WEB ONLY 1P-0694, Japanese

  • 体格決定に関与するEphA4シグナル経路の解析
    新井大貴, 澤田貴宏, JING Xuefeng, 宮嶋正康, CHEN Qingfa, 古島謙亮, 飯田啓二, 千原和夫, 坂口和成
    2012, 日本分子生物学会年会プログラム・要旨集(Web), 35th, WEB ONLY 4P-0284, Japanese

  • Takahiro Sawada, Xuefeng Jing, Yueqiang Zhang, Emi Shimada, Hideyuki Yokote, Masayasu Miyajima, Kazushige Sakaguchi
    Mar. 2010, GENES TO CELLS, 15(3) (3), 297 - 311, English

  • Ternary complex formation of EphA4
    澤田 貴宏, 京 雪楓, 宮嶋 正康
    2010, FGFR and FRS2α plays an important role in the proliferation of embryonic neural stem/progenitor cells Genes Cells 15, 297 - 311
    [Refereed]

  • 新規成長ホルモン不応性成長障害の発症機序
    宮嶋正康, 京雪楓, 澤田貴宏, 島田栄美, 飯田啓二, 村垣泰光, 千原和夫, 坂口和成
    (一社)日本骨代謝学会, 2009, 日本骨代謝学会学術集会プログラム抄録集, 27th, 175 - 175, Japanese

  • Eph‐FGFR‐FRS2αの複合体を介するシグナル伝達
    澤田貴宏, JING Xuefeng, 横手秀行, ZHANG Yueqiang, 島田栄美, 坂口和成
    2008, 生化学, 3P-0295, Japanese

  • GHシグナル伝達不全に基づく小人症モデルとしてのEphA4ノックアウトマウス
    宮嶋正康, 京雪楓, 村垣泰光, 飯田啓二, 千原和夫, 澤田貴宏, 張月強, 坂口和成
    日本疾患モデル学会, 01 Aug. 2007, 日本疾患モデル学会記録, 23(Supplement) (Supplement), 77 - 77, Japanese

  • EPhA4‐FGF受容体の複合体を介するシグナル伝達
    澤田貴宏, 重松康之, 京雪楓, 張月強, 藤田浩二, 横手秀行, 坂口和成
    和歌山医学会, 31 Dec. 2006, 和歌山医学, 57(4) (4), 174 - 175, Japanese

  • 坂口 和成, 澤田 貴宏, 京 雪楓
    (一社)日本内分泌学会, Apr. 2006, 日本内分泌学会雑誌, 82(1) (1), 39 - 39, Japanese

  • H Yokote, K Fujita, XF Jing, T Sawada, ST Liang, L Yao, XM Yan, YQ Zhang, J Schlessinger, K Sakaguchi
    Dec. 2005, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 102(52) (52), 18866 - 18871, English, International magazine

  • R Kodama, T Kondo, H Yokote, Jing, X, T Sawada, M Hironishi, K Sakaguchi
    Dec. 2005, GENES TO CELLS, 10(12) (12), 1211 - 1219, English

  • XM Yan, H Yokote, XF Jing, L Yao, T Sawada, YQ Zhang, S Liang, K Sakaguchi
    May 2005, GENES TO CELLS, 10(5) (5), 489 - 502, English, International magazine

■ Lectures, oral presentations, etc.
  • Molecular mechanisms of EphA4-mediated signal modulation of the growth hormone (GH)-Insulin-like growth factor 1 (IGF1) axis
    Takahiro Sawada
    ENDO2013, Jun. 2013, English, International conference
    Oral presentation

  • Signaling through the ternary complex of EphA4, FGFR, and FRS2α
    Takahiro Sawada
    2nd Eph/Ephrins and Cancer Meeting, Jun. 2010, English, International conference
    Poster presentation

  • FGF23 Function of Reducing the Phosphate (Pi) Uptake Is Mediated by Receptors Other than the FGFR-Klotho Complex in OK-E cells
    ASBMR 28th Annual Meeting, 2006
    Poster presentation

■ Affiliated Academic Society
  • 日本分子生物学会

■ Research Themes
  • New Insights into the GH-IGF1 axis of Signal Transduction: Elucidation of the Molecular Interactions
    Jing Xuefeng, Frank Stuart J.
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Wakayama Medical University, 01 Apr. 2013 - 31 Mar. 2017
    We previously reported that EphA4, a member of the Eph family of RTK, is an important modulator of growth hormone (GH) signaling, leading to augmented synthesis of IGF1 for postnatal body growth. We report here the molecular interactions of EphA4, GH receptor (GHR), JAK2 and STAT5B. EphA4 binds to GHR at both its extracellular and intracellular domains and phosphorylates GHR when stimulated with a ligand. The cytoplasmic domain of EphA4 binds to the carboxy-terminus of JAK2. STAT5B binds to the amino-terminal kinase domain of EphA4. Ligand-activated EphA4 and JAK2 phosphorylate each other and STAT5B, but JAK2 does not appear to phosphorylate EphA4-bound STAT5B. Ligand-activated EphA4 induces the nuclear translocation of STAT5B in a JAK2-independent manner. GHR expression is required for the activation of STAT5B signaling, even via the JAK2-independent pathway. These findings suggest the molecular mechanisms by which ephrin/EphA4 signaling enhances the canonical GH-IGF1 axis.

  • 統合的・革新的がんゲノム病理診断システム開発
    西原広史, 澤田貴宏, 船山貴智, 王磊, 杉野弘和
    公益財団法人 北海道科学技術総合振興センター, イノベーション創出研究支援事業 スタートアップ研究補助金, Apr. 2014 - Mar. 2016, Coinvestigator

  • Studies on a novel signaling pathway that mediates postnatal body growth
    SAKAGUCHI Kazushige, SAWADA Takahiro, FURUSHIMA Kenryo, JING Xuefeng, MIYAJIMA Masayasu, ARAI Daiki, MIWA Hideto
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Wakayama Medical University, 01 Apr. 2012 - 31 Mar. 2015
    The growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis mediates postnatal body growth. The GH receptor has been regarded as the sole receptor that mediates the JAK2/STAT5B signal toward IGF1 synthesis. Here, we report a signaling pathway that regulates postnatal body growth through EphA4, a member of the Eph family of receptor tyrosine kinases and a mediator of the cell-cell contact-mediated signaling. EphA4 forms a complex with the GH receptor, JAK2, and STAT5B and enhances Igf1 expression predominantly via the JAK2-dependent pathway, with some direct effect on STAT5B. Mice with a defective Epha4 gene have a gene dose-dependent short stature and low plasma IGF1 levels. Pituitary Gh mRNA and plasma GH levels were not reduced. IGF1 injection rescued the phenotype of Epha4-KO mice. These findings suggest that the local cell-cell contact-mediated ephrin/EphA4 signal is as important as the humoral GH signal in IGF1 synthesis and body size determination.

  • Development of a risk-organ-shifting technique during radiation therapy, with gel spacer
    KISHI KAZUSHI, SAWADA Takahiro, SAKAGUCHI Kazuya, SATO Morio, CHIBA Akihiro
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Exploratory Research, Wakayama Medical University, 28 Apr. 2011 - 31 Mar. 2015
    We developed a risk organ-shifting method by a spacer gel injection between the target and the normal organ, and enabled to deliver higher dose to the target with a further decreased normal organ dose. By basic experiments including migration assay we determined several appropriate patterns of gel selection, injection site selection, combination of single or fractionated irradiation, and injection method. Clinically, we most treated patients with prostate cancer with Tomotherapy or Brachytherapy providing efficient rectal avoidance. By gel spacer injection, the mean target dose was escalated to 83Gy from 74Gy while the rectal D2cc was decreased to 45Gy from 72Gy. We also enabled the similar dose delivery in safe to post operative recurrence of the prostate cancer. Furthermore, reirradiation treatment was safely processed by the gel spacer injection providing a curative dose delivery. To date some of these were already published.

  • GH-IGF1軸シグナル伝達系新規分子機構
    澤田 貴宏
    公益財団法人 武田科学振興財団, 医学系研究奨励（基礎）, 2014 - 2015, Principal investigator
    Competitive research funding

  • 生後の成長障害に関与する新規シグナル伝達機構の発見－GH-IGF1軸定説への挑戦
    坂口和成, 澤田貴宏, 宮嶋正康
    公益財団法人 内藤記念科学振興財団, 内藤記念科学奨励金・研究助成, 2013 - 2014, Coinvestigator

  • 体格形成に関与するGHシグナル定説への挑戦
    澤田 貴宏
    公益財団法人 上原記念生命科学財団研, 研究奨励金, 2012 - 2013, Principal investigator
    Competitive research funding

  • Genetic and molecular analysis of growth retardation caused by growth hormone insensitivity
    JING Xuefeng, SAKAGUCHI Kazushige, SAWADA Takahiro, MIYAJIMA Masayasu, CHIHARA Kazuo, IIDA Keiji
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Wakayama Medical University, 2009 - 2012
    GH is regarded as an essential hormone for postnatal body growth that mainly works through IGF1 production in liver and other tissues, and the whole signaling process is named GH-IGF1 axis. We identified EphA4 as an essential binding partner of GHR. EphA4 binds to GHR and augments activation of the JAK2/STAT5B pathway. In addition, EphA4 directly binds to and phosphorylates STAT5B. Through these interactions, EphA4 transcriptionally enhances IGF1 production in liver cells as well as in others. Epha4 KO mice show short stature in an Epha4 gene dose-dependent fashion, and respond well to IGF1 but not to GH treatment.

  • Development of a new regenerative treatment for Parkinson's disease by way of inducing proliferation, migration, and differentiation of neural stem cells in situ
    SAKAGUCHI Kazushige, MIWA Hideto, MIYAJIMA Masayasu, SAWADA Takahiro, JING Shuefeng
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Wakayama Medical University, 2007 - 2010
    Adult mouse brain has two neurogenic areas that contain neural stem/progenitor cells (NSPC). They can differentiate to nerve cells, astrocytes, and oligodendrocytes. Recent studies demonstrated that neural stem cells in the subventricular zone send extensions to the lateral ventricle and receive signals. Parkinson's disease, a neurodegenerative disorder, can be treated by supplying dopamine to improve symptoms, but this cannot be a curative treatment. Sooner or later, the dopaminergic neurons degenerate and become incapable of produce dopamine, resulting in deterioration of symptoms. Fetal nigral tissue transplantation can be one of the candidates of curative treatment, but is not regarded as a standard method due to ethical problems and difficulty in obtaining enough amount of such tissue. ES cells and iPS cells can be differentiated to dopaminergic cells, but the extent of differentiation and occasional occurrence of tumors must be controlled before applying to human. Immuno-rejective reactions and ethical problems must be controlled. Degeneration of neurons in the nigrostriatal tract deplete striatal dopamine and causes Parkinson's disease. Striatum is located close to the lateral ventricle, suggesting that the subventricular neural stem cells are the good candidates for the treatment of this disease by causing proliferation, migration and differentiation. In the current project, we examined whether Eph/ephrin signaling system can be used to induce these phenomenon for the treatment of Parkinson's disease in rats and marmosettes. In rats, injection of clustered ephrin-A1 into the lateral ventricle could induce NSPC proliferation, migration and differentiation to dopaminergic neurons, and angiogenesis in the striatum. These effects resulted in behavioral improvement of rats with hemilateral nigrostriatal lesion. The histological and behavioral improvement lasted at least for 12 weeks. Marmosettes have so small a ventricle that it was difficult to inject clustered ephrin-A1 into the lateral ventricle. However, multiple injection of ephrin-A1 in and around the lateral ventricle improved the animal behavior as measured by Supermex. Recombinant ephrin-A1 fused with the coiled-coil domain of cartilage oligomeric matrix protein was produced in E. coli, but the product was not soluble and precipitated in water, probably due to formation of large multimers. Because of these results, we used the authentic method of clustering ephrin-A1-Fc by anti-IgG(Fc) antibody.

  • Takahiro SAWADA
    Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid for Scientific Research(若手研究(B)), 若手研究(B), 和歌山県立医科大学, 2007 - 2010, Principal investigator
    We demonstrated previously that FGFRs and EphA4 trans-activate each other by forming a heterodimer, and augment downstream signals through FRS2α, a major docking protein of FGFRs, and MAP kinase. Based on these studies, I have studied the interaction domains among EphA4, FGFRs and FRS2α, and trans-phosphorylation partners of the two receptor tyrosine kinases. EphA4 interacts directly with and phosphorylates not only FGFRs but also FRS2α. From these interaction studies, it has become clear that EphA4, FGFR and FRS2α compose a ternary complex, which plays an important role in proliferation and differentiation of neural stem cells. Furthermore, I also found that FGFR directly activates ephexin1, a downstream molecule of EphA4, which regulates migration and morphological changes of neuronal cells through activation of Rho family. These studies show that the interaction of EphA4 with FGFR functions as a molecular mediator for neural cell proliferation, migration and differentiation.
    Competitive research funding

  • 神経幹細胞増殖分化促進薬剤の脳室内注入によるパーキンソン病治療法の開発
    京雪楓, 坂口和成, 澤田貴宏, 三輪英人
    独立行政法人科学技術振興機構, 地域イノベーション創出総合支援事業重点地域研究開発推進プログラム 「シーズ発掘試験」, 2006 - 2007, Coinvestigator

  • チロシンキナーゼ型受容体を介する新規細胞情報伝達系の機能解析
    その他の研究制度, 2004
    Competitive research funding

■ Industrial Property Rights
  • 中枢神経障害治療剤及び中枢神経障害の治療方法
    坂口 和成, 京 雪楓, 三輪 英人, 澤田 貴宏
    JP2008051632, 01 Feb. 2008, 財団法人大阪産業振興機構, WO2008-093827, 07 Aug. 2008
    Patent right
    IRI

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