総合医科学研究所　難病治療学
  1. 研究者リスト
  2. 土田 邦博

土田 邦博

ツチダ クニヒロ  (Kunihiro Tsuchida)

基本情報

所属
藤田医科大学 医科学研究センター 難病治療学 教授
学位
博士（医学）(京都大学)
Ph.D.(Kyoto University)
研究者番号
30281091
J-GLOBAL ID
200901025890179259
researchmap会員ID
0000107006
筋骨格系疾患、糖尿病・肥満、神経変性疾患等の治療の難しい疾患の病態解明と治療法開発に関する研究を行っています。 モデル動物、ノンコーディングRNAの解析、RNA-seqやプロテオミクス等の網羅的解析、微量細胞の分取と分化培養，エクソソームを中心としたナノテクノロジーの医学応用等の先端技術を駆使して難病の病態生理の解明と治療法の基盤確立を目指した研究に取り組んでいます。

研究キーワード

 21

研究分野

 11

経歴

 9
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学歴

 2

委員歴

 10
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受賞

 3

論文

 168
  • Hiroshi Ageta, Tomoki Nishioka, Hisateru Yamaguchi, Kunihiro Tsuchida, Natsumi Ageta-Ishihara
    Molecular brain 17(1) 57-57 2024年8月15日  
    Discovery of novel post-translational modifications provides new insights into changes in protein function, localization, and stability. They are also key elements in understanding disease mechanisms and developing therapeutic strategies. We have previously reported that ubiquitin-like 3 (UBL3) serves as a novel post-translational modifier that is highly expressed in the cerebral cortex and hippocampus, in addition to various other organs, and that 60% of proteins contained in small extracellular vesicles (sEVs), including exosomes, are influenced by UBL3. In this study, we generated transgenic mice expressing biotinylated UBL3 in the forebrain under control of the alpha-CaMKII promoter (Ubl3Tg/+). Western blot analysis revealed that the expression of UBL3 in the cerebral cortex and hippocampus was 6- to 7-fold higher than that in the cerebellum. Therefore, we performed immunoprecipitation of protein extracts from the cerebral cortex of Ubl3+/+ and Ubl3Tg/+ mice using avidin beads to comprehensively discover UBL3 interacting proteins, identifying 35 new UBL3 interacting proteins. Nine proteins were annotated as extracellular exosomes. Gene Ontology (GO) analysis suggested a new relationship between sEVs and RNA metabolism in neurodegenerative diseases. We confirmed the association of endogenous UBL3 with the RNA-binding proteins FUS and HPRT1-both listed in the Neurodegenerative Diseases Variation Database (NDDVD)-and with LYPLA1, which is involved in Huntington's disease, using immunoprecipitation (IP)-western blotting analysis. These UBL3 interacting proteins will accelerate the continued elucidation of sEV research about proteins regulated by novel post-translational modifications by UBL3 in the brain.
  • Setsuko Komatsu, Azzahrah Diniyah, Wei Zhu, Masataka Nakano, Shafiq Ur Rehman, Hisateru Yamaguchi, Keisuke Hitachi, Kunihiro Tsuchida
    International journal of molecular sciences 25(15) 2024年7月27日  
    Salt stress is a serious problem, because it reduces the plant growth and seed yield of wheat. To investigate the salt-tolerant mechanism of wheat caused by plant-derived smoke (PDS) solution, metabolomic and proteomic techniques were used. PDS solution, which repairs the growth inhibition of wheat under salt stress, contains metabolites related to flavonoid biosynthesis. Wheat was treated with PDS solution under salt stress and proteins were analyzed using a gel-free/label-free proteomic technique. Oppositely changed proteins were associated with protein metabolism and signal transduction in biological processes, as well as mitochondrion, endoplasmic reticulum/Golgi, and plasma membrane in cellular components with PDS solution under salt stress compared to control. Using immuno-blot analysis, proteomic results confirmed that ascorbate peroxidase increased with salt stress and decreased with additional PDS solution; however, H+-ATPase displayed opposite effects. Ubiquitin increased with salt stress and decreased with additional PDS solution; nevertheless, genomic DNA did not change. As part of mitochondrion-related events, the contents of ATP increased with salt stress and recovered with additional PDS solution. These results suggest that PDS solution enhances wheat growth suppressed by salt stress through the regulation of energy metabolism and the ubiquitin-proteasome system related to flavonoid metabolism.
  • Hideo Hagihara, Hirotaka Shoji, Satoko Hattori, Giovanni Sala, Yoshihiro Takamiya, Mika Tanaka, Masafumi Ihara, Mihiro Shibutani, Izuho Hatada, Kei Hori, Mikio Hoshino, Akito Nakao, Yasuo Mori, Shigeo Okabe, Masayuki Matsushita, Anja Urbach, Yuta Katayama, Akinobu Matsumoto, Keiichi I Nakayama, Shota Katori, Takuya Sato, Takuji Iwasato, Haruko Nakamura, Yoshio Goshima, Matthieu Raveau, Tetsuya Tatsukawa, Kazuhiro Yamakawa, Noriko Takahashi, Haruo Kasai, Johji Inazawa, Ikuo Nobuhisa, Tetsushi Kagawa, Tetsuya Taga, Mohamed Darwish, Hirofumi Nishizono, Keizo Takao, Kiran Sapkota, Kazutoshi Nakazawa, Tsuyoshi Takagi, Haruki Fujisawa, Yoshihisa Sugimura, Kyosuke Yamanishi, Lakshmi Rajagopal, Nanette Deneen Hannah, Herbert Y Meltzer, Tohru Yamamoto, Shuji Wakatsuki, Toshiyuki Araki, Katsuhiko Tabuchi, Tadahiro Numakawa, Hiroshi Kunugi, Freesia L Huang, Atsuko Hayata-Takano, Hitoshi Hashimoto, Kota Tamada, Toru Takumi, Takaoki Kasahara, Tadafumi Kato, Isabella A Graef, Gerald R Crabtree, Nozomi Asaoka, Hikari Hatakama, Shuji Kaneko, Takao Kohno, Mitsuharu Hattori, Yoshio Hoshiba, Ryuhei Miyake, Kisho Obi-Nagata, Akiko Hayashi-Takagi, Léa J Becker, Ipek Yalcin, Yoko Hagino, Hiroko Kotajima-Murakami, Yuki Moriya, Kazutaka Ikeda, Hyopil Kim, Bong-Kiun Kaang, Hikari Otabi, Yuta Yoshida, Atsushi Toyoda, Noboru H Komiyama, Seth G N Grant, Michiru Ida-Eto, Masaaki Narita, Ken-Ichi Matsumoto, Emiko Okuda-Ashitaka, Iori Ohmori, Tadayuki Shimada, Kanato Yamagata, Hiroshi Ageta, Kunihiro Tsuchida, Kaoru Inokuchi, Takayuki Sassa, Akio Kihara, Motoaki Fukasawa, Nobuteru Usuda, Tayo Katano, Teruyuki Tanaka, Yoshihiro Yoshihara, Michihiro Igarashi, Takashi Hayashi, Kaori Ishikawa, Satoshi Yamamoto, Naoya Nishimura, Kazuto Nakada, Shinji Hirotsune, Kiyoshi Egawa, Kazuma Higashisaka, Yasuo Tsutsumi, Shoko Nishihara, Noriyuki Sugo, Takeshi Yagi, Naoto Ueno, Tomomi Yamamoto, Yoshihiro Kubo, Rie Ohashi, Nobuyuki Shiina, Kimiko Shimizu, Sayaka Higo-Yamamoto, Katsutaka Oishi, Hisashi Mori, Tamio Furuse, Masaru Tamura, Hisashi Shirakawa, Daiki X Sato, Yukiko U Inoue, Takayoshi Inoue, Yuriko Komine, Tetsuo Yamamori, Kenji Sakimura, Tsuyoshi Miyakawa
    eLife 12 2024年3月26日  
    Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.
  • Atsushi Ohashi, Masashi Nakatani, Hideo Hori, Shigeru Nakai, Kunihiro Tsuchida, Midori Hasegawa, Naotake Tsuboi
    Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 27(6) 1023-1027 2023年12月  
    Abstract Introduction Indoxyl sulfate (IS) is a protein‐bound uremic toxin that causes uremic sarcopenia. IS has poor dialysis clearance; however, the addition of a binding competitor improves its removal efficiency. Methods Dialysis experiments were performed using N‐acetyl‐l‐tryptophan (L‐NAT) instead of l‐tryptophan (Trp) using pooled sera obtained from dialysis patients. The molecular structures of L‐NAT and Trp were similar to that of IS. Therefore, we examined whether Trp and L‐NAT were involved in muscle atrophy in the same manner as IS by performing culture experiments using a human myotube cell line. Results The removal efficiency of L‐NAT was the same as that of Trp. However, L‐NAT concentrations in the pooled sera increased at the end of the experiment. Trp (1 mM) decreased the area of human myocytes, similar to IS, whereas L‐NAT did not. Conclusion L‐NAT is a binding competitor with the ability to remove protein‐bound IS while preventing sarcopenia.
  • Setsuko Komatsu, Taiki Kimura, Shafiq Ur Rehman, Hisateru Yamaguchi, Keisuke Hitachi, Kunihiro Tsuchida
    International journal of molecular sciences 24(18) 2023年9月6日  
    Salt stress of soybean is a serious problem because it reduces plant growth and seed yield. To investigate the salt-tolerant mechanism of soybean, a plant-derived smoke (PDS) solution was used. Three-day-old soybeans were subjected to PDS solution under 100 mM NaCl for 2 days, resulting in PDS solution improving soybean root growth, even under salt stress. Under the same condition, proteins were analyzed using the proteomic technique. Differential abundance proteins were associated with transport/formaldehyde catabolic process/sucrose metabolism/glutathione metabolism/cell wall organization in the biological process and membrane/Golgi in the cellular component with or without PDS solution under salt stress. Immuno-blot analysis confirmed that osmotin, alcohol dehydrogenase, and sucrose synthase increased with salt stress and decreased with additional PDS solution; however, H+ATPase showed opposite effects. Cellulose synthase and xyloglucan endotransglucosylase/hydrolase increased with salt and decreased with additional PDS solution. Furthermore, glycoproteins decreased with salt stress and recovered with additional treatment. As mitochondrion-related events, the contents of ATP and gamma-aminobutyric acid increased with salt stress and recovered with additional treatment. These results suggest that PDS solution improves the soybean growth by alleviating salt stress. Additionally, the regulation of energy metabolism, protein glycosylation, and cell wall construction might be an important factor for the acquisition of salt tolerance in soybean.
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MISC

 186
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書籍等出版物

 15
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講演・口頭発表等

 112
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担当経験のある科目(授業)

 10
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所属学協会

 11
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共同研究・競争的資金等の研究課題

 27
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その他

 3
  • ① 筋萎縮抑制薬開発。 ② 多種類の筋萎縮誘導モデル、新規二分脊椎モデル。 ③ ヒト正常筋や動物由来の高品質・高純度の筋幹細胞、筋支持細胞の取得技術 その細胞を用いた薬剤探索（筋の脂肪化抑制、骨化抑制）の応用実績。 ④ 乳がん由来細胞を用いた、転移・接着性の分子機構解析（エクソソーム分泌、ホルモン感受性、接着分子制御など）。
  • 近隣の高等学校から依頼を受け、難病研究の説明や研究室の見学を行なっている。
  • 教育内容・方法の工夫 医学部生や医療系コメディカルの講義を一部担当。講義内容の理解の助けとし、毎年改訂している。オンライン講義・対面講義の両方に工夫をしている。 医学部の少人数制の生物学の英語テキストの抄読会を行っている。 リサーチマインドを持った医学部学生のSRP（ステューデントリサーチャープログラム）で受け入れと研究指導を行なっている。 医療科学部卒論生の研究指導、発表会に向けた助言を行っている。

教育内容・方法の工夫（授業評価等を含む）

 3
  • 件名
    医学修士
    開始年月日
    2020/04/01
    概要
    オンライン講義で、医学部以外の出身者が医学的知識をつけれるように、わかりやすい説明を心がけている。
  • 件名
    Human Biology
    開始年月日
    2013/04/01
    概要
    医学部2年生の少人数制の英語抄読。医学英語力と発表能力のコンピタンス向上に向け、毎年工夫を凝らしている。2020年度はWeb講義として行っており、それに即した教育法を実践している。
  • 件名
    病理学
    開始年月日
    2010/04/01
    概要
    毎年ファイルを改定し、理解度チェックを入れるなど工夫している。
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