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Ueno Masaki

  • Faculty of Medicine
  • School of Medicine
  • Professor
Last Updated :2025/04/24

Researcher Information

J-Global ID

Research Interests

  • Neuropathology   Pathology   Neuropathology   Pathology   

Research Areas

  • Life sciences / Experimental pathology
  • Life sciences / Neuroanatomy and physiology

Academic & Professional Experience

  • 2013  - 香川大学医学研究院, 教授
  • 2013  - 香川大学医学研究院, 教授
  • 1999 - 2002  Kagawa Medical University
  • 2002  - 香川医科大学医学部 病理学講座(現 香川大学医学部 炎症病理学）, 助教授
  • 1995 - 1999  赤心会赤沢病院, 医師
  • 1993 - 1994  康生会武田病院, 医師
  • 1994  ニューヨーク州立発達障害基礎研究所
  • 1992 - 1993  医仁会武田総合病院, 医師
  • 1988 - 1992  京都大学医学部大学院医学研究科, 大学院生
  • 1986 - 1988  宇部興産中央病院, 医師
  • 1985 - 1986  京都大学医学部神経内科, 研修医

Education

  •        - 1985  Kyoto University  Faculty of Medicine  医学科
  •        - 1985  Kyoto University  Faculty of Medicine  Department of Medical Science

Association Memberships

  • THE JAPANESE SOCIETY OF NEUROPATHOLOGY   THE JAPANESE SOCIETY OF PATHOLOGY   

Published Papers

Books etc

  • 中枢神経 (非腫瘍性疾患病理アトラス)
    新井 信隆 (Contributor)文光堂 2024/03 9784830604942 304p 2
  • Glymphatic system
    上野 正樹 (ContributorGlymphatic system 総論)中外医学社 2019/01
  • 血管生物学と疾患
    上野 正樹 (ContributorCerebral amyloid angiopathyー血管周囲領域を介した脳組織間液ならびに脳脊髄液の排出との関連で)文光堂 2017/08
  • 認知症
    高尾, 昌樹 (Contributor認知症の動物モデルに関して教えてください)中外医学社 2016/12 9784498129863 vii, 435p
  • Pediatric cancer
    Springer 2012
  • The pineal gland and melatonin
    NOVA 2012 9781608767175
  • Alzheimer's disease pathogenesis
    InTech 2011

Conference Activities & Talks

  • ヒトおよびマウス脳の脈絡叢上皮細胞間におけるE-カドヘリンの局在について  [Not invited]
    竹林玄太;千葉陽一;村上龍太;若松敬司;宮井由美;松本晃一;荻野祐一;上野正樹
    第113回日本病理学会総会  2024/03  名古屋国際会議場  豊國伸哉
  • 神経変性と脳のバリア機能  [Not invited]
    上野正樹;千葉陽一;村上龍太;宮井由美;松本晃一;若松敬司
    第113回日本病理学会総会  2024/03  名古屋国際会議場  豊國伸哉
  • 悪性症候群後に発症した小脳変性症の１剖検例  [Not invited]
    千葉陽一;太田仁士;吉井りつ;野中和香子;松川昭博;佐藤明;上野正樹
    第113回日本病理学会総会  2024/03  名古屋国際会議場  豊國伸哉
  • 新生児遷延性肺高血圧症を合併したBohring-Opitz症候群の一剖検例  [Not invited]
    宮井由美;千葉陽一;有岡誠;松本晃一;村上龍太;中村信嗣;日下隆;上野正樹
    第113回日本病理学会総会  2024/03  名古屋国際会議場  豊國伸哉
  • Phospholipase A and acyltransferase 1 (PLAAT1) 欠損は高脂肪食誘導性の肥満と脂肪肝を緩和する  [Not invited]
    佐々木すみれ; Rahman SM Khaledur; 宇山徹;Hussain Zahir; Sikder Mphammad Mamun; 財賀大行;太田健一;三木寿美;星野克明;上野正樹;村上誠;上田夏生
    第96回日本生化学会大会  2023/11  福岡  日本生化学会
  • マウスCaMKKbスプライシングバリアントの生化学的・組織学的解析  [Not invited]
    大塚里美;宮井由美;美馬光志;曲正樹;千葉陽一;水津太;阪上洋行;上野正樹;徳光浩
    第96回日本生化学会  2023/11  福岡国際会議場  住本英樹
  • 脈絡叢上皮細胞におけるGLUT12の局在およびSGLT2の発現  [Not invited]
    若松敬司;千葉陽一;宮井由美;村上龍太;松本晃一;上野正樹
    若手支援技術講習会  2023/09  名古屋市公会堂  先端モデル動物支援プラットフォーム
  • 認知機能増悪機序の解明を目指して  [Invited]
    上野正樹
    先端モデル動物支援若手技術講習会  2023/09  名古屋市公会堂  先端モデル動物支援プラットフォーム（2023年度文部科学省学術変革領域研究）
  • Gene disruption of the phospholipid-related enzyme PLAAT1 improves high-fat diet-induced obesity and hepatic lipid accumulation  [Not invited]
    Uyama T; Sasaki S; Rahman SMK; Hussain Z; Sikder MM; Saiga H; Ohmura-Hoshino M; Ohta K; Miki Y; Hoshino K; Ueno M; Murakami M; Ueda N.
    The 2nd Trilateral Symposium on SDGs  2023/08  Kagawa  Kagawa University
  • 脈絡叢上皮細胞におけるGLUT12の局在  [Not invited]
    若松敬司;千葉陽一;宮井由美;村上龍太;松本晃一;上野正樹
    第64回日本神経病理学会総会学術研究会  2023/07  神戸国際会議場  望月秀樹
  • Phospholipase A and acyltransferase (PLAAT) 1 deficiency ameliorates obesity and hepatic lipid accumulation in mice  [Not invited]
    Sumire Sasaki; S.M. Khaledur Rahman; Toru Uyama; Zahir Hussain; Mohammad Mamun Sikder; Hiroyuki Saiga; Ken-ichi Ohta; Yoshimi Miki; Katsuaki Hoshino; Masaki Ueno; Makoto Murakami; and Natsuo Ueda
    33rd Annual Symposium of the International Cannabinoid Research Society  2023/06  Toronto, Canada  the International Cannabinoid Research Society
  • 集学的治療が有効であった肝細胞癌皮膚転移・歯肉転移の一例  [Not invited]
    西田 衣里; 田所 智子; 森下 朝洋; 琢磨 慧; 中原 麻衣; 大浦 杏子; 藤田 浩二; 三村 志麻; 谷 丈二; 小野 正文; 正木 勉; 宮井 由美; 千葉 陽一; 松本 晃一; 村上 龍太; 上野 正樹
    第59回日本肝臓学会総会  2023/06  奈良県コンベンションセンター  吉治仁志
  • 生体内におけるPhospholipase A and acyltransferase1の機能解析  [Not invited]
    佐々木すみれ; Rahman SM Khaledur; 宇山徹;Hussain Zahir; Sikder Mphammad Mamun; 財賀大行;太田健一;三木寿美;星野克明;上野正樹;村上誠;上田夏生
    第64回日本生化学会中国・四国支部例会  2023/05  愛媛  日本生化学会中国・四国支部
  • 家族性発症が疑われるtau, TDP-43, FUS陰性の前頭側頭葉変性症の1剖検例  [Not invited]
    千葉陽一;吉井りつ;太田仁士;佐藤明;上野正樹
    第48回臨床神経病理懇話会  2022/11  徳島大学医学部  和泉唯信
  • High-Fat Diet-Induced Hepatic Lipid Accumulation is Decreased in PLAAT1- Deficient Mouse  [Not invited]
    S. M. Khaledur Rahman; Uyama Toru; Hussain Zahir; Mohammad Mamun Sikder; Saiga Hiroyuki; Ohta Kenichi; Hoshino Katsuaki; Ueno Masaki; Miki Yoshimi; Murakami Makoto; and Ueda Natsuo
    第95回日本生化学会大会  2022/11  名古屋  日本生化学会
  • Accumulation of N-acyl-phosphatidylethanolamines in brain ischemia by cytosolic phospholipase A2ε  [Not invited]
    Toru Uyama; Zahir Hussain; Katsuya Morito; S. M. Khaledur Rahman; Mohammad Mamun Sikder; Tamotsu Tanaka; Kenichi Ota; Masaki Ueno; Hiroo Takahashi; Tohru Yamamoto; Makoto Murakami; and Natsuo Ueda
    32nd Annual Symposium of the International Cannabinoid Research Society  2022/06  Galway  the International Cannabinoid Research Society
  • ヒト剖検脳の脈絡叢石灰化巣におけるオステオポンチンとコラーゲン蛋白の免疫組織学的発現について  [Not invited]
    若松敬司;千葉陽一;村上龍太;宮井由美;松本晃一;上野正樹
    第63回日本神経病理学会総会学術研究会  2022/06  京都市 京都府立京都学・歴菜館/稲盛記念会館  伊東恭子
  • cPLA2εは脳障害部位でN-アシル-ホスファチジルエタノールアミンを合成する  [Not invited]
    宇山 徹; Zahir Hussain; 森戸克弥; 田中 保; 太田健一; 上野正樹; 村上 誠; 上田夏生
    第64回日本脂質生化学会  2022/06  東京  日本脂質生化学会
  • PLAAT1 Deficiency Alleviates High Fat Diet-Induced Hepatic Lipid Accumulation in Mice  [Not invited]
    S.M. Khaledur Rahman; Toru Uyama; Zahir Hussain; Mohammad Mamun Sikder; Hiroyuki Saiga; Kenichi Ota; Katsuaki Hoshino; Masaki Ueno; Yoshimi Miki; Makoto Murakami; and Natsuo Ueda
    第63回日本生化学会中国・四国支部例会  2022/05  徳島  日本生化学会中国・四国支部
  • 精巣捻転症ラットモデルによる精巣虚血再灌流障害に関する研究 病理組織学的分析と遺伝子プロファイリング  [Not invited]
    形見 祐人; 藤井 喬之; 田中 彩; 上野 正樹; 鈴木 辰吾; 三木 崇範; 下野 隆一
    第122回日本外科学会定期学術集会  2022/04  熊本城ホール  馬場秀夫
  • 臨床病理検討会（メソトレキセート関連リンパ増殖性疾患）  [Not invited]
    上野正樹
    第125回日本内科学会四国地方会  2021/12  Web開催（香川大学医学部担当）  日本内科学会四国地方会
  • 脳虚血時に蓄積するN-アシル-ホスファチジルエタノールアミンはcPLA2εによって合成される  [Not invited]
    宇山 徹; Zahir Hussain; 森戸克弥; 田中 保; 太田健一; 上野正樹; 村上 誠; 上田夏生
    日本ビタミン学会第73回大会  2021/06  東京  日本ビタミン学会
  • 血液脳関門障害血管における分子メカニズム解明から血管性認知症の治療へ  [Not invited]
    第57回日本病理学会秋期特別総会  2011
  • The mechanism of blood-brain barrier dysfunction in vascular dementia.  [Not invited]
    The Second Congress of Asian Society of Neuropathology  2011
  • Therapeutic targets for vascular dementia  [Not invited]
    NeuroTalk-2010  2010
  • Gene analyses in vessels with blood-brain barrier impairment  [Not invited]
    XVIIth International Congress of Neuropathology  2010
  • 稀な肉眼像を呈した回盲部原発のdiffuse large B cell lymphomaの一例  [Not invited]
    第95回日本病理学会総会  2006
  • 新生仔豚の海馬脳血管におけるアミロイドベータ蛋白様triosephosphate isomerase の沈着について  [Not invited]
    第95回日本病理学会総会  2006
  • 右第3指に発生した皮下腫瘤の一切除例  [Not invited]
    第90回日本病理学会 中四国支部学術集会  2006
  • Listeria monocytogenes敗血症による化膿性脳脊髄膜炎、心外膜炎の１剖検例  [Not invited]
    第94回日本病理学会総会  2005
  • 抗炎症脂質N-アシルエタノールアミンを生成する新規ホスホリパーゼD型酵素(NAPE-PLD)のcDNAクローニングと発現部位の解析  [Not invited]
    生体防御機能異常ワークショップ2005  2005
  • Hypoxia Inducible Factor (HIF-1) によるT細胞機能の制御  [Not invited]
    第２６回日本炎症・再生医学会  2005

MISC

  • 精巣捻転症ラットモデルによる精巣虚血再灌流障害に関する研究 病理組織学的分析と遺伝子プロファイリング
    形見 祐人; 藤井 喬之; 田中 彩; 上野 正樹; 鈴木 辰吾; 三木 崇範; 下野 隆一  日本外科学会定期学術集会抄録集  122回-  SF  -1  2022/04
  • 悪性症候群後に小脳失調症を呈した一症例のHSP免疫染色を含む病理学的検討
    太田仁士; 吉井りつ; 野中和香子; 千葉陽一; 上野正樹  日本神経学会学術大会プログラム・抄録集  61st-  2020
  • Sodium/glucose cotransporter 2 is expressed in choroid plexus epithelial cells and ependymal cells
    千葉陽一; 杉山康憲; 西望; 野中和香子; 河内真知; 上野正樹  日本病理学会会誌  109-  (1)  2020
  • Cerebral amyloid angiopathy－ 血管周囲領域を介した脳組織間液ならびに脳脊髄液の排出との関連で
    上野正樹; 千葉陽一; 村上龍太; 松本晃一; 藤原龍史; 植村直哉  病理と臨床  35-  (8)  724  -728  2017/08  [Invited]
  • 血液脳脊髄液関門におけるアミロイドベータおよび糖等の輸送体の局在について
    上野正樹; 千葉陽一; 村上龍太; 松本晃一  香川県医師会誌  69-  2016
  • 前頭側頭葉優位の脳萎縮と広範なLewy小体の出現をみたNiemann-Pick病C型の一剖検例
    千葉 陽一; 小森 拓; 吉田 太; 足立 香織; 難波 栄二; 武井 史郎; 石井 さなえ; 上野 正樹; 細川 昌則; 島田 厚良  日本病理学会会誌  104-  (1)  435  -435  2015/03
  • アルツハイマー病モデルマウスの認知機能に対する外傷性脳損傷の影響
    KISHIMOTO YASUSHI; SHISHIDO HAJIME; KUBOTA TAKASHI; UENO MASAKI; TAMIYA TAKASHI; KAWAI NOBUYUKI; KIRINO YUTAKA  日本薬学会年会要旨集(CD-ROM)  134th-  (3)  ROMBUNNO.28PMM-096  -149  2014/03
  • 低酸素性虚血性脳症における脳循環・代謝の病態生理とこれからの治療戦略
    日下 隆; 安田 真之; 小谷野 耕佑; 中村 信嗣; 中村 信; 神内 済; 三木 崇範; 上野 正樹; 磯部 健一; 伊藤 進  日本周産期・新生児医学会雑誌  49-  (4)  1172  -1175  2013/12
  • Gene analyses in vessels with blood-brain barrier impairment
    M. Ueno; M. Onodera; H. Sakamoto  BRAIN PATHOLOGY  20-  75  -75  2010/09
  • Gene analyses in vessels with BBB impairment
    M. Ueno; M. Onodera; H. Sakamoto  XVII INTERNATIONAL CONGRESS OF NEUROPATHOLOGY (ICN)  93  -95  2010  [Refereed]
  • 上田 夏生; 趙 麗穎; 坪井 一人; 岡本 安雄; 荒木 伸一; 上野 正樹  ビタミン  82-  (5)  353  -353  2008
  • Hypoxia Inducible Factor-1(HIF-1)によるT細胞機能の制御
    冨田 修平; 小野 純一郎; Rahman Md.Mustafizur; 上野 正樹; 平井 宗一; 植木 正明; Gonzalez Frank; 高浜 洋介  炎症・再生  25-  (4)  390  -390  2005/07
  • 脳組織構築におけるHypoxia Inducible Factor-1a(HIF-1a)の役割
    冨田 修平; 上野 正樹; 北浜 有希; 岩永 康之; 阪本 昌美; 植木 正明; 影山 龍一郎; 上田 夏生; Gonzalez Frank J.; 高浜 洋介  生化学  76-  (10)  1386  -1386  2004/10
  • M Ueno; H Sakamoto; Akiguchi, I; M Hosokawa  SENESCENCE-ACCELERATED MOUSE (SAM): AN ANIMAL MODEL OF SENESCENCE  1260-  341  -344  2004  [Refereed]
  • 脳組織構築におけるHypoxia Inducible Factor-1a(HIF-1a)の役割
    冨田 修平; 上野 正樹; 阪本 昌美; 植木 正明; 影山 龍一郎; 上田 夏生; Gonzalez Frank; 高浜 洋介  炎症・再生  23-  (6)  455  -455  2003/11
  • 高血圧自然発症ラット(SHR)の血液脳関門機能の領域による違いについて
    上野 正樹; 阪本 晴彦; 冨本 秀和; 秋口 一郎  Neuropathology : official journal the Japanese Society of Neuropathology  23-  109  -109  2003/05
  • 脳虚血実験モデル動物における血液脳関門障害について
    上野 正樹; 冨本 秀和; 秋口 一郎; 脇田 英明; 阪本 晴彦  Neuropathology : official journal the Japanese Society of Neuropathology  22-  147  -147  2002/05
  • Ultrastructure of the Aging Tissues in SAM Mice Morphological Basis of the Senescence Acceleration and Age-dependent Degenerative Disorders
    HOSOKAWA M.; UENO M.; NISHIKAWA T.; CHIBA Y.; AKIGUCHI I.  Electron-microscopy  34-  55  -58  1999/11
  • 老化の超微形態像 : SAM系統マウスにおける老化促進と老年性退行変性疾患発症の機構
    細川 昌則; 上野 正樹; 西川 智文; 千葉 陽一; 秋口 一郎  日本臨床電子顕微鏡学会誌  32-  S54  1999/10
  • Toshio Kawamata; Ichiro Akiguchi; Kiyoshi Maeda; Chikako Tanaka; Keiichi Higuchi; Masanori Hosokawa; Toshio Takeda  Microscopy Research and Technique  43-  (1)  59  -67  1998/10
  • マウス脳室周囲領域に於ける血管透過性について
    上野 正樹; 阪本 晴彦; 秋口 一郎  Neuropathology : official journal the Japanese Society of Neuropathology  18-  28  -28  1998/05
  • 老化促進モデルマウスの嗅球における血液脳関門機能の特殊性 : 微小血管の超微形態的特徴
    上野 正樹; 阪本 晴彦; 秋口 一郎  Neuropathology : official journal the Japanese Society of Neuropathology  17-  274  -274  1997/05
  • Neuropathological studies on strains of senescence accelerated mouse with age related deficits in learning and memory
    AKIGUCHI, I; H YAGI; A SHIMADA; M UENO; M TAKEMURA; T KITABAYASHI; N SERYU; T KAWAMATA; S NAKAMURA; T TAKEDA  ALZHEIMER'S AND PARKINSON'S DISEASES  44-  395  -400  1995  [Refereed]
  • BETA/A4 PROTEIN-LIKE IMMUNOREACTIVE GRANULAR STRUCTURES IN THE BRAIN OF SENESCENCE-ACCELERATED MOUSE (SAM)
    M TAKEMURA; S NAKAMURA; AKIGUCHI, I; M UENO; N OKA; S ISHIKAWA; A SHIMADA; J KIMURA; T TAKEDA  SAM MODEL OF SENESCENCE  1062-  355  -358  1994  [Refereed]
  • AGE-RELATED MORPHOLOGICAL-CHANGES IN THE BRAIN OF SENESCENCE-ACCELERATED MOUSE (SAMP8)
    AKIGUCHI, I; H YAGI; M UENO; M TAKEMURA; T KITABAYASHI; N SERIU; T KAWAMATA; S NAKAMURA; A SHIMADA; T TAKEDA  SAM MODEL OF SENESCENCE  1062-  67  -72  1994  [Refereed]

Awards & Honors

  • 2011 日本病理学会学術研究賞
     JPN

Research Grants & Projects

  • 先端モデル動物支援プラットフォーム
    日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2022/04 -2028/03 
    Author : 武川 睦寛; 井上 純一郎; 中村 卓郎; 高田 昌彦; 清宮 啓之; 山田 泰広; 八尾 良司; 荒木 喜美; 阿部 学; 伊川 正人; 高橋 智; 真下 知士; 小林 和人; 小林 憲太; 井上 謙一; 豊國 伸哉; 二口 充; 神田 浩明; 上野 正樹; 宮崎 龍彦; 高松 学; 宮川 剛; 高雄 啓三; 池田 和隆; 新田 淳美; 尾藤 晴彦; 虫明 元; 旦 慎吾; 馬島 哲夫; 田代 悦; 堂前 直; 松本 健; 川田 学; 田原 栄俊; 掛谷 秀昭; 澤崎 達也; 松浦 正明
  • 脈絡叢と海馬の関連に注目した糖尿病増悪状態における認知機能低下機序の解明
    文部科学省：科学研究費助成事業
    Date (from‐to) : 2024/04 -2027/03 
    Author : 上野 正樹
  • 低分子グアーガム分解物と次世代善玉菌のシンバイオティクス療法によるIFALD予防
    文部科学省：科学研究費助成事業
    Date (from‐to) : 2023/04 -2026/03 
    Author : 藤井 喬之
     
    腸管不全の合併症である腸管不全合併肝障害(Intestinal failure-associated liver disease：IFALD)は致死率の高い重篤な疾患であるが、有効な治療法は確立されていない。IFALDの発症に腸と肝臓および腸内細菌叢の相互作用が関与していることが分かってきた。食物繊維である低分子グアーガム分解物(Partially hydrolyzed guar gum ：PHGG)は腸内細菌叢の調整作用に優れ、様々な生理活性がある。本研究はIFALDモデルを用いてParabacteroides に肝保護作用があるかを検証し、さらにPHGGのシンバイオティクスとしての有効性を示すことを目指す。
  • グリア細胞老化におけるglutaminolysisの役割と神経変性への寄与の解明
    文部科学省：科学研究費助成事業
    Date (from‐to) : 2023/04 -2026/03 
    Author : 千葉 陽一
     
    老化細胞が老年性疾患の発症に重要であることが明らかとなってきた。最近、老化細胞の生存がグルタミン分解に依存しており、これを阻害すると老化細胞が死に、老年性疾患が改善することが示された。本研究では、老化細胞におけるグルタミン分解の重要性が脳の老化細胞においても普遍的であるか検証する。グリア細胞の老化に伴うグルタミン分解酵素の発現変化を明らかにし、グルタミン分解を抑えることにより老化グリア細胞が除去できるか検討する。また、グルタミン分解亢進が神経変性過程を促進する可能性を検証する。本研究により、グルタミン分解抑制による神経変性疾患の治療法開発につながる発見を目指す。
  • 新規の近赤外光時間分解測定を用いた新生児の脳浮腫評価
    日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2022/04 -2025/03 
    Author : 日下 隆; 三木 崇範; 上野 正樹; 中村 信嗣; 光家 努; 星 詳子; 森本 絢; 中尾 泰浩; 有岡 誠
  • Elucidation of molecular mechanisms of neurodegeneration caused by dysfunctional senescent astrocytes
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2019/04 -2022/03 
    Author : Chiba Yoichi
     
    There is an increasing awareness of the contribution of senescent cells to age-related pathologies. Recent studies suggested astrocytes exhibit cellular senescence phenotypes in aged human brain and Alzheimer’s disease. However, the mechanisms that senescent astrocytes affect pathophysiology of brain aging and age-related neurodegenerative diseases remain unclear. Here we investigated changes in protein expression in senescent astrocyte using 2-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Cellular senescence, assessed by senescence-associated β-galactosidase (SA-β-Gal) staining, immunoblotting with p21 and lamin B1 antibodies, and γH2AX immunocytochemistry, was efficiently induced by treating mouse primary astrocytes with 200 μM H2O2 for 2 hours. 2D-DIGE analyses revealed that 5 protein spots showed a significant increase in H2O2-treated astrocytes compared with control, whereas 6 spots exhibited significant decrease in H2O2-treated cells.
  • New therapy for neonatal resuscitation using hydrogen gas
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2019/04 -2022/03 
    Author : 中村 信嗣; 安田 真之; 小谷野 耕佑; 三木 崇範; 上野 正樹; 日下 隆; 太田 健一
     
    今年度は、新生仔豚4頭を用いて、6時間の水素ガス吸入を行った。心臓機能と脳循環との関係を調べるために、心臓超音波による心機能検査を低酸素負荷前から負荷後まで継続して行い、低酸素虚血が与える心機能への経時的影響及び水素ガス吸入による心機能回復効果について調べた。その結果、低酸素虚血負荷により左心機能よりも右心機能の低下が早期より起こり、その結果、静脈還流が減り、脳血液量が増加していることが考えられた。また、水素ガス吸入は、蘇生後の心機能回復に寄与している可能性が高いことがわかった。
  • Advanced Animal Model Support
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas ― Platforms for Advanced Technologies and Research Resources
    Date (from‐to) : 2016 -2021 
    Author : 井上 純一郎; 今井 浩三; 中村 卓郎; 井上 純一郎; 高田 昌彦; 山田 泰広; 高橋 智; 伊川 正人; 﨑村 建司; 荒木 喜美; 八尾 良司; 真下 知士; 小林 和人; 豊國 伸哉; 鰐渕 英機; 今井田 克己; 二口 充; 上野 正樹; 宮崎 龍彦; 神田 浩明; 尾藤 晴彦; 宮川 剛; 高雄 啓三; 池田 和隆; 虫明 元; 清宮 啓之; 長田 裕之; 旦 慎吾; 井本 正哉; 川田 学; 田原 栄俊; 吉田 稔; 松浦 正明; 牛嶋 大; 吉田 進昭
     
    ①総括支援活動 : 若手技術講習会を9月11日にオンラインにて開催した。108名の参加者があり、活発な討論が行われた。成果発表会は2月2日にハイブリッド形式で開催し、被支援者による研究成果の紹介を中心に行われ252名の参加者があった。支援拠点の研究者と被支援者が分担で執筆した本支援活動を紹介する「マウス・ラットモデル作製・解析プロフェッショナル」を出版した。 ②モデル動物作製支援活動 : 前・後期2回の公募で申請のあった計116件について一次・二次審査を行い、学術的に優れた83件の申請を採択した。それぞれの採択者と個別に協議し、最適な遺伝子改変技術を用いて、遺伝子改変マウスおよびラットを迅速に作製し、研究リソースとして提供した。 ③病理形態解析支援活動 : 55件の申請を受け、3回の審査の結果、35件に関して病理形態解析を実施した。研究の方向性を裏付ける多くの成果が得られた。論文の図の作成など、論文が受理されるまで支援を実施した。 ④生理機能解析支援活動 : 行動学的解析では26件、薬理学的解析では16件、光技術による操作解析では9件、多機能電極・計測データ解析では13件の申請について支援し、コロナ禍にもかかわらず、4つの支援の全てで、昨年度よりも支援数を増やした。支援は、動物モデルにおける病態・生理学的基盤の解明推進などに寄与し、Nat Commun誌、iScience誌などに成果が発表された。 ⑤分子プロファイリング支援活動 : 化合物の分子プロファイリング48件、阻害剤キット配付18件、RNA干渉キット配付・siRNAデザイン合成5件、shRNAライブラリー探索2件、分子間相互作用解析1件(計74件、支援提供回数として505回)に加え、高次情報解析、動物実験に向けた技術相談を行った。被支援者と全班員の意見交換を目的としたユーザー会議を開催した。
  • Relationship between hyperbilirubinemia and cerebral oxygen metabolism in newborn infants.
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2020/03 
    Author : Kusaka Takashi
     
    Neonatal hyperbilirubinemia is the unique physiological phenomenon in human. Its biological significance depends on the role of bilirubin as a radical scavenger during neonatal period, when the brain oxygen metabolism develops rapidly. We validated the methods for measurements of both liver glucuronidation and cerebral oxygen consumption in human neonates. We found that serum conjugated bilirubin and bilirubinⅨαare useful for assessments of liver glucuronidation two weeks after birth, because the secretion of conjugated bilirubin is stable at that time. Further, we investigated relationships between cerebral Hb oxygen saturation (ScO2) by near-infrared spectroscopy and Hb oxygen saturation of the internal jugular vein or femoral artery in children with congenital heart diseases, found ScO2 is useful for assessing cerebral oxygenation in neonates.
  • Identification of CSC-specific markers for non-small cell lung cancer and development of lung cancer root therapy
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2017/04 -2020/03 
    Author : Liu Dage
     
    The treatment results for advanced stage lung cancer are still poor, and there is an urgent need to develop new treatments for advanced stage lung cancer. In recent years, the introduction of the concept of cancer stem cells (CSCs) has led to a better understanding of the mechanisms of cancer development, metastasis, and recurrence. Eradication of cancer stem cells is essential for tumor elimination and prevention of recurrence, and cancer stem cells have become important targets for cancer treatment. In this study, by inducing epithelial-mesenchymal transition, we established a cancer stem cell line for non-small cell lung cancer, which is difficult to identify and isolate cancer stem cells, and obtained basic data for new cancer treatment aiming at radical cure of cancer.
  • Elucidation of the mechanism of promoting dementia caused by diabetes mellitus, focusing on the transport dynamics of glucose through the choroid plexus
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2017/04 -2020/03 
    Author : Ueno Masaki
     
    Urate transporters, GLUT9 and URAT1, which are believed to be related with reduction of oxidative stress, were located on apical and basal cytoplasmic membranes of choroid plexus epithelium (Nerosci Lett 2017, 659, 99-103). An efflux transporter of iron which is related to oxidative damage, ferroportin, as well as hepcidin and hephaestin were located in the cytoplasm of choroid plexus epithelium (Neuropathol 2020, 40, 75-83). In addition, sodium/glucose cotransporter 2 (SGLT2), through which glucose is transported based on sodium concentration gradient, was located in the cytoplasm of choroid plexus epithelium (Neuropathol 2020, in press).
  • Spontaneously Generated Large Adipose Flap in an in vivo Tissue-Engineering Chamber
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2015/04 -2018/03 
    Author : Hamamoto Yusuke; UENO Masaki; TAMAI Motogi; KOGURE Tetsukuni; TANAKA Yoshio
     
    The present study clarified 1) the reproducibility of creating an adipose flap, 2) the time-course of adipogenesis, 3) the long-term stability of a generated adipose flap, and 4) the mechanism of adipogenesis in an in vivo chamber. The chamber was used as a protected space for tissue engineering, the vascular pedicle as a vascular source, the collagen sponge as a scaffold, and PRP and c-bFGF as growth factors.Results)The ratios of the vascular pedicle and adipose tissue in the generated tissue were 14.8%, 47% and 80% at 4, 8, and 12 weeks, respectively. The adipose flap in Group 12w maintained its volume and shape for five months following pedicle transfer. Conclusions:Adipose flaps were spontaneously generated at 12 weeks with reproducibility, and showed long-term stability. Fibroblast-like cells recruited from the vascular pedicle was thought to contribute to the adipogenesis in the tissue-engineering chamber.
  • Could neuronal cell senescence be a pathogenetic factor for age-associated neurodegenerative diseases?
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : Chiba Yoichi
     
    To investigate whether neuronal cell senescence contributes to the pathogenesis of age-associated neurodegenerative diseases, we analyzed the expression of cell senescence markers in cultured primary cortical neurons from E17 embryos of SAMP8 mice, a model for age-associated neurodegeneration. Primary neurons from mouse embryos were successfully maintained in serum-free media for up to 8 weeks. The ratio of senescence-associated β-galactosidase-positive neurons from SAMP8 mice was significantly increased after 28 days in vitro (DIV) when compared to those from control SAMR1 mice. The expression of γ-H2AX, a marker for DNA damage foci, was increased in nuclei of cultured neurons after 28 DIV, although no significant difference between neurons from SAMP8 and SAMR1 mice. Other cell senescence markers, such as heterochromatin-associated mH2A and lipid peroxidation product 4-HNE, did not show significant difference between neurons from SAMP8 and SAMR1 mice.
  • The effects of hydrogen gas inhalation for hypoxic-ischemic encephalopathy in piglets.
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2017/03 
    Author : Kusaka Takashi
     
    The aim of this study is to evaluate the effectiveness of free radical scavenger (edaravone, EV) combined with hypothermia (HT) for hypoxic-ischemic (HI) brain injury, and the safety of hydrogen gas inhalation in neonatal piglets. The following results had been reported. At first, there was a positive linear correlation between changes in cerebral blood volume and low-amplitude aEEG duration during 12 h after the insult in the no-therapy group, but a negative linear correlation between these two parameters in the HT group. Secondly, both HT and HT+EV groups showed lower histopathological cerebral damages compared to that of no-therapy, especially in gray and white matter. However, HT+EV did not show lower damages compared to HT. Lastly, hydrogen gas inhalation had no effects on circulatory and metabolic activities, especially cerebral hemodynamics and oxygen metabolism, and cortical electrical activity. Therefore, hydrogen gas is likely to be used safely in neonatal medicine.
  • Effects of overdose of fructose on dementia
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : UENO Masaki
     
    Immunoreactivity of GLUT5 and GLUT8 was located in epithelial cells of the choroid plexus and ependymal cells. Immunoreactivity of GLUT8 was located in the cytoplasm of astrocytes and microglia. It is likely that intravascular substance including sugars was transported to periventricular areas. These findings suggest that intravascular fructose migrates to periventricular areas. Culture experiments under high concentration of fructose for short and long periods were conducted by evaluating not only survival rates, production of reactive oxygen species (ROS), and effects on the outgrowth of cultured neurons, but also survival rates and ROS production of cultured microglia. Although the survival rate of cultured neurons for a long period had decreased slightly, other parameters were significantly changed.
  • Effect of platelet rich plasma and bFGF in in-vivo tissue engineered vascularized soft tissue flap
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2016/03 
    Author : TANAKA Yoshio; HAMAMOTO yhusuke; UENO Masaki
     
    (Purpose) Evaluate the effectiveness of platelet rich plasma (PRP) in tissue-engineered vascularized soft tissue flaps in in-vivo chamber. (Materials and methods) Animals: Japanese white male rabbit, Chamber was used as protected space for tissue engineering, pedicle vascular bundle for vascular source, collagen sponge for scaffold of cell migration. PRP and bFGF were additionally used as growth factors and the most effective combination to get a lager and more matulated granulation tissue was evaluated. Results) Additional use of PRP prevented the white, bean-curd-like debris, which was thought to be degradation of collagen sponge as a result of foreign body reaction in the previous experiments. The combination of activated PRP and controlled release bFGF showed the most effectiveness for generation of vascularized soft tissue flaps.These results suggested the usefulness of PRP in the clinical application of in vivo tissue-engineering vascularized soft tissue flap.
  • Preparation of the guideline for biomarkers-based personlized treatment for patients with advanced lung cancer
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2016/03 
    Author : Liu Dage; Nakano Jun; Tokunaga Masayosi; Yokomise Hiroyasu; Ueno Masaki
     
    Tailor-made medicine is important for improving the result of cancer treatment. Cancer related biomarkers were comprehensively analysied and biomarkers-based chemotherapy were used into the clinical management in our institude. We tried to establish a simple and standardized [biomarkers-bassed ailor-made medicine selectting system] for widespreading the benefit of biomarkers. The in vitro 3D drug sensitivity test (CD-DST method) and prespective study were performed to verification of the value of biomarkers. These results of our study have been adopted by domestic and international conferences, and the usefness of biomarkers-bassed ailor-made medicine for patients with advanced-stage lung cancer was appealled abroad.
  • Treatment strategy of neonatal hypoxic-ischemic encephalopathy using by newborn piglets asphyxia model
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2016/03 
    Author : Saneyuki Yasuda; KOYANO Kosuke; MIKI Takanori; UENO Masaki; NAKAMURA Shinji; KUSAKA Takashi
     
    In these studies, we found that combining the cerebral blood volume (CBV) with amplitude-integrated EEG (aEEG) is a more effective guide to control hypoxic/ischemic (HI) insult in a newborn piglet model than aEEG alone, to produce a consistent degree of survivable neuropathological damage. Next, we found that an early CBV increase and longer low-ampitude EEG after insult indicates severe brain injury. Finally, we revealed that Edaravone (a free radical scavenger) reduced histologic neuronal damage related to HI loading in our piglet HI model. However, we also found the histopathological damage, especially kidney tissue. We have to consider the systemic impact by Edaravone.
  • Effect of high O2 concentration to generated tissue in tissue engineering chamber
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2012/04 -2015/03 
    Author : HAMAMOTO Yusuke; TANAKA Yoshio; UENO Masaki; TAMAI Motoki; KOGURE Tetsukuni
     
    We previously described induction of spontaneous tissue generation by implanting a collagen matrix and a ligated pedicle (arteriovenous bundle) into a hollow porous chamber (Tissue Engineering Chamber: TEC) in vivo in rabbits. They hypothesized that increased tissue volume could be obtained by the application of ASCs and/or by increasing the oxygen tension. In rabbits, a saphenous arteriovenous pedicle and a collagen sponge were inserted into a porous chamber in the groin. Rabbits were housed in either 20% (control) or 60% (normobaric oxygenation: NBO) atmospheric oxygen for the first 7 days, and then returned to normoxia. Samples harvested at 4 weeks were histological analyzed for tissue regeneration in chamber. And each was compared with and without ASCs. All patent chambers grew tissue. Tissue volume in ASCs with NBO groups was significant greater than that in the respective groups of the others.
  • Combined therapy using drug resistant relative molecular-suppressing vector and anticancer drug
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2010 -2012 
    Author : LIU Dage; YOKOMISE Hiroyasu; UENO Masaki
     
    （No Summary）
  • Strategy for hypoxic-ischemic encephalopathy in newborn infants to reduce oxygen free radicals by adjusting hydrogen and oxygen
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2010 -2012 
    Author : KUSAKA Takashi; UENO Masaki; MIKI Takanori; YASUDA Saneyuki; IWASE Takashi; NISHIDA Tomoko
     
    In these studies, we found that combining the cerebral blood volume (CBV) with amplitude-integrated EEG (aEEG) is a more effective guide to control hypoxic/ischemic (HI) insult in a newborn piglet model than aEEG alone, to produce a consistent degree of survivable neuropathological damage. Next, we found that an early CBV increase and longer low-ampitude EEG after insult indicates severe brain injury. Finally, we revealed that Edaravone (a free radical scavenger) reduced histologic neuronal damage related to HI loading in our piglet HI model.
  • Development of new therapies for vascular dementia
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2010 -2012 
    Author : UENO Masaki; SAKAMOTO Haruhiko; KOH Seiryu
     
    The expression of osteopontin, CD36, and LDL receptor (LDLR) was turned out to be increased in vessels showing blood-brain barrier (BBB) dysfunction. We could productsynthetic peptides of osteopontin, an antibody for osteopontin, virus vector expressing osteopontin. The expression of CD36 was turned out to be increased in the vessels showing BBB dysfunction in brains of hypertensive rats and senescence accelerated mice. Drugs inducing the reduction of CD36 or LDLR expression may be useful for the therapy against vascular dementia. In addition, angiotensin receptor blockers (ARBs) reduced vascular damage including the BBB damage, suggesting that the usage of ARBs with osteopontin may be effective for the therapy against vascular dementia.
  • Experimental study of vascularized flap preparation in a tissue engineering chamber
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2009 -2011 
    Author : TANAKA Yoshio; UENO Masaki; HAMAMOTO Yhusuke; KOGURE Tetukuni
     
    We evaluated a method to regenerate soft tissue flap in a tissue engineering chamber(TEC) as a site of regeneration by concomitantly using an AV bundle, artificial dermis, FGF-2, and platelet-rich plasma(PRP). The samples were divided into control, FGF-2, non-activated PRP, activated PRP, non-activated PRP+ FGF-2, and activated PRP+ FGF-2 groups, and the amount of regenerated tissue, degree of maturation of organization were evaluated. Results : Non-activated PRP induced more satisfactory regeneration of vascularized soft tissue than Activated PRP. Regenerated tissue with the highest degree of maturation was obtained in the non-activated PRP+ FGF-2group. The results indicate that the simultaneous use of non-activated PRP and FGF-2 is advantageous for the regeneration of vascularized soft tissue in a TEC.
  • Developmental changes in cerebral oxygen metabolism during neonatal period
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2007 -2008 
    Author : KUSAKA Takashi; UENO Masaki; MIKI Takanori; NAMBA Masanori; NISHIDA Tomoko; IWASE Takashi; OKUBO Kensuke; KUBOI Toru
     
    新生児期の脳酸素代謝の特徴は、早産児は正期産児と比較し脳血液量、酸素代謝量が低く、在胎週数と共に増加する。しかし低酸素虚血性脳症や脳室内出血を来たす病態では、出後早期には脳の循環自動調節能が破綻し、脳血液量が増加し、酸素消費量も低下する事が示唆された。特に低酸素虚血性脳症のエネルギー代謝障害時には、軽症例では酸素消費量が減少するが、重症例では脳血流上昇後に脳浮腫が進行し虚血が進行すると考えられた。
  • Cancer gene therapy of Wnt and TM4SF to inhibit progression of lung cancer
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2006 -2008 
    Author : HUANG Cheng-long; ISHIKAWA Sinya; YOKOMISE Hiroyasu; UENO Masaki
     
    Wnt抑制ベクター作製のため, shRNA配列をpBAsi-hU6 DNAプラスミドベクターに組入れ, COS-TPC法でWnt抑制shRNA発現アデノウィルスベクターを作製した. Wnt2b抑制ベクターは, in vitro実験でWnt2b高発現癌細胞株に対して細胞障害活性を認め, Wnt2b高発現癌細胞株を移植した担癌ヌードマウスによる実験でも強力な抗腫瘍効果を認めた. 我々はTM4SFのメンバーであるCD9 の発現誘導アデノウィルスベクターも用いて, 癌転移抑制遺伝子治療の研究も行い, 機能解析を行っている.
  • Tailor-made chemotherapy for non-small cell lung cancers
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2006 -2007 
    Author : LIU Dage; HUANG Cheng-long; ISHIKAWA Shinya; YOKOMISE Hiroyasu; UENO Masaki
     
    In order to improve the clinical outcome of patients with non-small cell lung cancer (NSCLC), we have been performing "tailor-made chemotherapy", the selection of the effective chemotherapy treatment based on evaluation of biomarkers associated with chemo-responsiveness (Huang, et. Al., Future Oncol 2006).Biomarkers associated with 5-FU responsiveness are its target enzyme TS, activating enzyme OPRT, and catabolic enzyme DPD. We have found that low TS expression, high OPRT expression, and low DPD expression are independent good prognostic factors in NSCLC patients postoperatively treated with oral 5-FU (Nakano, et. Al., Br J Cancer 2006). On the other hand, because epidermal growth factor receptor (EGFR) gene mutations are reported to be associated with responsiveness of EGFR-specific TKIs, we developed the clinically useful protocol to evaluate the EGFR gene mutations (Liu, et. Al.,〓ncol Rep 2006). In addition, we performed comprehensive studies on the tumor suppressor gene p53, which is involved in tumor apoptosis (Huang, et. Al., Future Oncol 2007). Consequently, we demonstrated a reduced expression of HAUSP to be associated with the downregulation of the p53 protein and its targets, such as p21 and bax (Masuya, et. Al., J Pathol 2006). Furthermore, regarding the apoptosis inhibitor survivin, we have found that the E2F1 over-expression is associated with the TS and Survivin expression (Clin Cancer Res 2007), and that splicing variants of Survivin have different biological functions associated with carcinogenesis (Nakano, et. Al., Br J Cancer 2008).Comprehensive analysis using cDNA microarray assays revealed the Wnt pathway to be associated with carcinogenesis. In addition, we found that the intratumoral Wntl expression is a poor prognostic factor of NSCLC patients, through the induction of its targets, such as c-Myc and MMP-7 (Liu, et. Al., Lung Cancer 2007; Nakashima, et. Al., Oncol Rep 2008).
  • Cancer gene therapy using the let-7-inducing vector to inhibit K-ras signals
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2006 -2007 
    Author : ISHIKAWA Shinya; HUANG Cheng-long; LIU Dage; YOKOMISE Hiroyasu; UENO Masaki
     
    A reduced expression of let-7 has been reported to induce an overexpression of K-ras onco-protein. The overexpression of K-ras protein can induce tumor proliferation and angiogenesis. Therefore, we are performing an experimental study on the cancer gene therapy using let-7-inducing viral vectors. We evaluated the let-7 expression in cancer cell lines, and found that MAC10 is a cancer cell line with a reduced let-7 expression. We constructed let-7-inducing viral vectors using the shRNA (short hairpin RNA) type. We inserted the shRNA containing the let-7 sequence into pBApo-CMV vector to construct the let-7-inducing plasmid vector MIR09. The transfection of the MIR09 vector into MAC10 cells using the lipofection method demonstrated the effective induction of the let-7 : expression. Then, we constructed the let-7-inducing adenoviral vector. After the extraction of the sequence of "CMV IE promotor + shRNA" from the MIR09 vector, this was inserted into the cosmid vector pAxcwit. Then, the let-7-inducing adenoviral vector, let7-Ad5, was produced by the COS-TPC method. After confirming the structure and the transfection efficiency of this adenoviral vector, the let7-Ad5 vector was condensed and purified. Regarding the in vitro experiment of the gene therapy, the transfection of the let7-Ad5 vector into MAC10 cells induced the let-7 expression and inhibited the cell proliferation. In addition, we found the induction of the let-7 expression to down-regulate the protein expressions of K-ras and the c-Myc. We are performing additional experiments in other cancer cell lines with reduced let-7 expression. Furthermore, using the tumor-bearing nude mice made by the subcutaneous inoculation of MAC10 cells, we are studying an in vivo experiment of the let-7 gene therapy.
  • Elucidation of physiological finction of anandamide, an endogenous marijuana-like substance, in mammals
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2006 -2007 
    Author : OKAMOTO Yasuo; UEKI Masaaki; UENO Masaki
     
    N-Acylethanolamines (NAEs) constitute a large and diverse class of signaling lipids that includes the endogenous cannabinoid anandamide. It is widely accepted that in mammalian tissues all NAEs are principally released from their corresponding N-acyl phosphatidylethanolamines (NAPEs) by the catalysis by a membrane-associated phospholipase D generally abbreviated as NAPE-PLD. Recently, NAPE-PLD was identified as a candidate enzyme involved in the biosynthesis of NAEs by us. To understand the physiological and pathophysiological significance of anandamide and other bioactive NAEs in mammals, we generated and characterized mice with a targeted disruption in the NAPE-PLD gene (NAPE-PLD-1). (1) lb generate mice lacking NAPE-PLD, exon 3 of the NAPE-PLD gene was removed by Cre/loxP system. (2) NAPE-PLD-1- were born at the expected Mendelian frequency, were viable and healthy, and showed no overt differences in their cage behavior compared to wild type littermates. (3) RT-PCR and Western blotting with anti-NAPE-PLD antibodies confirmed the absence of NAPE-PLD mRNA and protein in tissues from NAPE-PLO-h. (4) Tissues from NAPE FED" showed significantly lower NAPE-PLD activity with an N-palmitoyl-PE as substrate compared to wild type tissues. (5) Significant reductions in the levels of saturated NAEs were observed in NAPE-PLO-I brains. On the other hand, complementary profiles of NAPEs were found in NAPE-PLD+/+ and NAPE-PLD-1- brains, with the latter samples possessing 15-20-fold higher levels of saturated N-acyl NAPEs, These data suggest that NAPE-PLD is a principal enzyme responsible for the conversion of NAPEs to NAEs in mammals.
  • Combined therapy using TS-suppressing vector and 5-FU
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2006 -2007 
    Author : UENO Masaki; HUANG Cheng-long; ISHIKAWA Shinya; YOKOMISE Hiroyasu
     
    Thymidylate synthase (TS) is a target molecule of 5-FU-derived anti-tumor drugs. We found a TS overexpression to be associated with the 5-FU resistance (Nakano, et. al., Br J Cancer 2006). Therefore, in order to develop the treatment against patients with TS-overexpressing cancers, we have been studying on the combined therapy with a TS-suppressing vector and 5-FU. First, to determine the effective siRNA sequence against TS, we synthesized several siRNAs. With the transfection of the siRNA into TS-overexpressing cells, such as A549 and MAC10, using the lipofection method, we determined the most effective siRNA sequence against TS. After the synthesize of shRNA (short hairpin RNA) based on this siRNA, we constructed a TS-suppressing shRNA plasmid vector by inserting the shRNA into the pBAsi-hU6 DNA plasmid vector with the human U6 promoter. Then, using the COS-TPC method, we constructed a TS-suppressing shRNA adenoviral vector (TSshRNA-Ad5). The transfection of TSshRNA-Ad5 into TS-overexpressing. lls, A549 and MAC10, resulted in more than 90% of knockdown of the TS gene expression. Then, we concentrated and purified the TSshRNA-Ad5. Next, we performed the MTT assay to evaluate the anti-tumor efficacy of the TSshRNA-Ad5 and 5-FU in A549 and MAC10 cells. Consequently, we found that the combined therapy with both TSshRNA-Ad5 and 5-FU had a stronger anti-tumor effect than the simple treatment of TSshRNA-Ad5 or 5-FU did. In order to confirm these results, we are performing the additional in vitro experiments using 5-FU-resistant cancer cells, such as NUGC-3/5-FU. In addition, we are also performing the in vivo experiment of the combined therapy with the TS-suppressing vector and 5-FU using the tumor-bearing nude mice. Furthermore, we found an E2F1 overexpression to induce the TS expression in non-small cell lung cancer (Huang, et. Al., Clin Cancer Res 2007).
  • Tailor-made therapy based on genetic analyses for non-small cell lung cancers
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2004 -2005 
    Author : LIU Dage; HUANG Cheng-long; YOKOMISE Hiroyasu; UENO Masaki
     
    We performed various genetic analyses in non-small cell lung cancer (NSCLC). Genetic mutations were evaluated for p53, K-ras, and epidermal growth factor receptor (EGFR). Quantitative RT-PCR assays were performed to determine gene expressions of HAUSP, ING1b, CD9, CD82, E-cadherin, thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD). In addition, immunohistochemistry was done to evaluate protein expressions of p53, mdm2, CD9CD82, E-cadherin, TS, DPD, VEGF-A, VEGF-C, the Ki-67 index, and the intratumoral microvessel density. Consequently, biomarkers associated with angiogenesis or metastasis, including a VEGF-A expression, a VEGF-C expression, and an E-cadherin expression, proved to be prognostic factors for early stage NSCLCs. On the other hand, the tumor proliferation rate and a TS expression were prognostic factors for advanced stage NSCLCs. In particular, the survival of patients with TS-negative tumors who were postoperatively treated with 5-FU derived antitumor agents was the highest among advanced stage NSCLCs. These results demonstrated the importance of multi-disciplinary therapy with effective chemotherapy, tailor-made therapy, even in advanced stage NSCLCs. We are performing prospective clinical studies on tailor-made therapy, using 5-FU derived agents against TS-negative and DPD-negative tumors, and Gefitinib against tumors with EGFR mutations. The prospective clinical study demonstrated UFT to be effective for TS-negative tumors. Recently, S-1 was developed for clinical use as a new 5-FU derived antitumor agents with a stronger DPD inhibitor. We will perform a further study to evaluate the efficacy of S-1 against TS-negative and DPD-positive NSCLCs. Furthermore, we studied gene expressions and protein expressions using cDNA microarray assays and proteomics in order to find new biomarkers associated with NSCLCs. Consequently, we have found the Wnt signal pathway to be associated tumor progression in NSCLCs.
  • Combined therapy using metastatic suppressor gene therapy and angiogenesis inhibitors for non-small cell lung cancers
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2004 -2005 
    Author : HUANG Cheng-long; YOKOMISE Hiroyasu; UENO Masaki
     
    We constructed the spontaneous metastasis model using the inoculation of tumor cell lines or tumor tissues into nude mice. The comprehensive analysis of expressions of tumor metastatic suppressor genes and angiogenesis factors revealed a reduced MRP-1/CD9 expression, a reduced KAI1/CD82 expression, and a reduced E-cadherin expression to be associated with pulmonary metastases. Regarding angiogenesis factors, a VEGF-A expression and a interleukin-8 expression were associated with intratumoral angiogenesis. In lung cancers, the HGF-cMet pathway was associated with the tumor proliferation, but not with angiogenesis (Br J Cancer 2004). The comprehensive analyses of gene expressions using cDNA microarray assays have demonstrated that the MRP-1/CD9 gene transduction suppresses the Wnt signal pathways (Oncogene 2004) and a WAVE2 expression (Oncogene 2006). Furthermore, we found the Wnt1 expression to be associated with the intratumoral VEGF-A expression, and the Wnt5a expression to be associated with the stromal VEGF-A expression (J Clin Oncol 2005). The finding that the MRP-1/CD9 transduction induces the down-regulation of VEGF-A, one of a Wnt target, suggested the possibility of the synergic effect of the combined therapy using metastatic suppressor gene therapy and angiogenesis inhibitors. Therefore, we performed experimental studies on combined therapy of metastatic suppressor gene therapy and angiogenesis inhibitors using the spontaneous metastasis model of nude mice. The adenoviral transfection of MRP-1/CD9 and KAI1/CD82 suppressed pulmonary metastases of tumors, respectively. TNP-470 and CGS27023A, angiogenesis inhibitors, also suppressed pulmonary metastases. Although TNP-470 inhibited tumor growth, but it caused weight loss as a side effect. However, we could not find any synergic effects in various types of the combined therapy of metastatic suppressor gene therapy and angiogenesis inhibitors.
  • Blood-brain barrier and dementia
    Date (from‐to) : 1988
  • 認知症性疾患における血液脳関門機能の役割
  • Blood-Brain Barrier dysfunction in dementing disorders

Teaching Experience

  • PathologyPathology Faculty of Medicine, Kagawa University

Committee Membership

  • 2021/06 - Today   The Japanese Society of Neuropathology   Executive Committee
  • 2005/04 - Today   The Japanese Society of Pathology   Councilor

Social Contribution

  • 原発不明癌の1剖検例
    Date (from-to) : 2023/09/06-2023/09/06
    Role : Lecturer
    Category : Lecture
    Sponser, Organizer, Publisher  : 坂出市医師会
    Event, Program, Title : 令和5年度坂出市医師会臨床病理検討会
    Others 坂出市医師会会館 坂出市医師会所属医師の先生方を対象に、原発不明癌の一例、との演題名での臨床病理検討会にて講演を行った。
  • Elucidation of pathogenesis of Dementia
    Date (from-to) : 2022/05/12
    Role : Lecturer
    Category : Visiting lecture
    Sponser, Organizer, Publisher  : Kagawa University

Academic Contribution

  • 日本神経病理学会（教育委員会委員長・理事）
    Date (from-to) :2023/04/01-Today
    Role: Planning etc
    Type: Academic society etc
    Organizer, responsible person: 柿田明美
    日本神経病理学会の教育委員会委員長（理事）として活動しています。
  • 日本病理学会
    Date (from-to) :2023/04/01-2024/03/31
    Role: Others
    Type: Academic society etc
    Organizer, responsible person: 小田義直
    病理医・研究医の育成とリクルート委員会委員
  • 老化促進モデルマウス（SAM）学会
    Date (from-to) :2023/04/01-2024/03/31
    Role: Planning etc
    Type: Academic society etc
    Organizer, responsible person: 細川昌則
    会計担当幹事
  • Free Radical Biology and Medicine
    Date (from-to) :2024/03/20-2024/03/25
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: Elsevier
  • Advanced Therapeutics
    Date (from-to) :2024/03/16-2024/03/22
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: Wiley
  • Diagnostics
    Date (from-to) :2024/01/31-2024/02/09
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • International Journal of Molecular Sciences
    Date (from-to) :2024/01/18-2024/01/19
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • Free Radical Biology and Medicine
    Date (from-to) :2023/12/30-2024/01/09
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: Elsevier
  • Neuropathology
    Date (from-to) :2023/12/27-2024/01/05
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: Wiley
  • International Journal of Molecular Sciences
    Date (from-to) :2023/11/29-2023/11/29
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • International Journal of Molecular Sciences
    Date (from-to) :2023/11/17-2023/11/20
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • Cells
    Date (from-to) :2023/10/30-2023/11/05
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • Biology
    Date (from-to) :2023/08/17-2023/09/26
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • Neuropathology
    Date (from-to) :2023/09/22-2023/09/23
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: Wiley
  • Diagnostics
    Date (from-to) :2023/09/15-2023/09/19
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • 第17回診断病理サマーフェスト
    Date (from-to) :2023/09/09-2023/09/10
    Role: Planning etc
    Type: Academic society etc
    Organizer, responsible person: 日本病理学会
    東京（恵比寿） EbiS303 テーマは神経で、最初のIntroductionを担当した
  • International Journal of Molecular Sciences
    Date (from-to) :2023/04/10-2023/07/13
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • Neuropathology
    Date (from-to) :2023/06/21-2023/07/01
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: Masaki Takao
  • International Journal of Molecular Sciences
    Date (from-to) :2023/04/11-2023/06/08
    Role: Peer review
    Type: Peer review etc
    Organizer, responsible person: MDPI
  • 第34回老化促進モデルマウス学会学術大会
    Date (from-to) :2019/07/14-2019/07/15
    Role: Planning etc
    Type: Academic society etc
    Organizer, responsible person: 香川大学医学部・炎症病理学

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