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HIDA Hideki

    Graduate School of Medical Sciences Department of Neurophysiology and Brain Science　Professor
Contact： hhidamed.nagoya-cu.ac.jp
Last Updated :2024/04/26

Researcher Information

URL

J-Global ID

Research Interests

  • 障害脳機能の再生・再建   リハビリテーションの基礎医学   発達障害児の基礎医学   ES細胞／iPS細胞を用いた細胞移植   

Research Areas

  • Life sciences / Neuroscience - general
  • Life sciences / Physiology

Academic & Professional Experience

  • 2009- 名古屋市立大学医学研究科 教授
  • 2003-2009 名古屋市立大学医学研究科 准教授
  • 2001-2003 名古屋市立大学医学部 講師
  • 1997-2001 名古屋市立大学医学部 助手
  • 1995-1997 シカゴ大学 ポストドクフェロー
  • 1995-1997 名古屋市立大学医学部 研究員

Education

  • 1991/04 - 1995/03  Nagoya City University  医学研究科
  • 1985/04 - 1991/03  Nagoya City University  Faculty of Medicine  医学科

Association Memberships

  • 日本情動学会   日本児童青年精神医学会   日本周産期・新生児医学会   北米神経科学会   日本神経科学会   日本生理学会   

Published Papers

MISC

Awards & Honors

  • 2000 日本生理学会奨励賞

Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2022/04 -2025/03 
    Author : 飛田 秀樹; 松川 則之; 小林 憲太
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2021/04 -2024/03 
    Author : 田尻 直輝; 飛田 秀樹; 安原 隆雄
     
    在胎32週以下の早産児に生じる脳性麻痺では、脳室周囲白質軟化症（PVL）が多い。発達段階の中枢神経系の未熟性に、低酸素虚血（H-I）が加わり、脳室周囲の白質が障害されることが、PVLの基本病態であると考えられている。PVLの病態は、H-Iに対する未熟脳の反応性と正常な脳発達の要素とが複雑に混在している。胎児脳におけるオリゴデンドロサイトの分化段階で、ヒトにおける在胎28週から32週は、ラットでは生後3日齢の脳内環境に相当する。この時期にH-Iを呈すると、分化途上のオリゴデンドロサイト後期前駆細胞（pre-OL）は選択的に障害を受けやすい。つまり、pre-OLの細胞死や分化抑制が起き、オリゴデンドロサイト前駆細胞（OPC）の成熟障害が生じることで、PVLの危険性が高まることが知られている。髄鞘を形成するオリゴデンドロサイトは、脳高次機能の発現に重要な役割を担い、pre-OL虚血障害による髄鞘形成障害は、運動機能と認知機能の生後発達と関連している。近年の周産期医療の進歩により、脳組織欠損（cyst）を認める重症型PVLは激減したが、MRIでも明らかなcystを認めない軽症型PVLが増加している。軽症型PVLでは、運動機能障害とともに発育後の認知機能障害も臨床上の大きな課題となっており、未だに根本的治療法は存在しない。 我々は、軽症型PVLの病態を良く反映する新生児低酸素虚血性白質障害（NWMI）モデルラットを確立し、PVLの根本的治療法の開発を目指している。本研究では、この疾患モデル動物を用いて、外部からOPCを補充することで、運動機能の改善に繋がるかどうか（実験１）、移植したOPCが脳内で、生存・生着・分化・成熟するかどうか（実験２）を検証した。また、発育期のリハビリテーション（以下、リハビリ）が成熟後の運動機能にどのような影響を与えるか（実験３）についても焦点を当てている。
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2021/04 -2024/03 
    Author : 佐藤 義朗; 飛田 秀樹; 湯川 博; 小野田 淳人
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2021/04 -2024/03 
    Author : 清水 健史; 飛田 秀樹
     
    本研究課題では、オリゴデンドロサイトで発生する力を可視化するために、蛍光共鳴エネルギー移動(FRET)システムを用いた張力センサープローブを使用し、蛍光寿命顕微鏡法を用いてFRET強度を計測した。 まず初めに、オリゴデンドロサイトがミエリンを形成する過程で産生される「力」の解析を試みた。中枢神経系には太い神経軸索と細い神経軸索が混在しているが、それぞれに適したミエリン形成をすることが高次脳機能の発現に極めて重要である。しかしながら、軸索径に応じたミエリン化の制御メカニズムは未だ明らかになっていない。そこで、ポリスチレン製ナノファイバーを異なる太さに調製し、それぞれに対してミエリン形成するオリゴデンドロサイトが惹起する「力」の計測を行った。その結果、太いファイバーに対してミエリン化しているオリゴデンドロサイト突起では、力の産生が大きく、また形成される接着斑のサイズが大きいことが明らかになった。また、単一のオリゴデンドロサイト内でもファイバー径に応じて張力の変化が検出されたことから、細胞の分化程度に依存しない物理的な現象であることが確認できた。 これらの結果から、太さの異なる軸索に応じてそれぞれ物理的な「力」が惹起され、接着斑から細胞内へシグナルが駆動され、ミエリン形成が制御される新しい機構が提唱された。これら結果を投稿し、リバイス実験を経て、学術雑誌への掲載に至った。
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2018/04 -2023/03 
    Author : 鈴木 元彦; 飛田 秀樹; 尾崎 慎哉; 中村 善久
     
    RNA干渉は二本鎖RNAと相補的な塩基配列をもつmRNAが分解される現象で、siRNA （smallinterfering RNA）という21-23bp塩基対の短い合成二本鎖RNAによって惹起される。また、近年制御性樹状細胞や制御性T細胞のみならず免疫反応を抑制 するB細胞（制御性B細胞）の存在が発見され注目されている。アレルギー反応はIgEを介して出現するが、B細胞はIgEを産生する細胞であり、アレルギー反応に おいて大変重要な役割を果たしている。以上を踏まえ、本研究において、私たちはsiRNAを導入することによりB細胞の修飾が可能かどうか、また制御性B細胞の 誘導が可能かどうかについて研究してきた。そして、B細胞にCD40に対するsiRNA（CD40 siRNA）を導入することによって、OVA抗原特異的CD40ノックダウンB細胞 の作製に成功した。以上を踏まえ、私たちはCOVA抗原特異的CD40ノックダウンB細胞をマウスに投与してその効果を研究した。その結果、COVA抗原特異的CD40ノックダウンB細胞をアレルギー感作前に投与することによってくしゃみ症状、鼻描き症状が有意に抑制されることが証明した。また、鼻粘膜の好酸球浸潤も有意に抑制されることが示された。
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2020/04 -2022/03 
    Author : 飛田 秀樹
     
    小脳-赤核路のウイルスベクター二重感染の最適化を行い、小脳-赤核路へウイルスベクターを効率的に二重感染させることが可能となった。 DREADD法を用いた小脳赤核路の神経遮断による上肢運動機能の評価では、ラット赤核へレトルウイルスベクター(FuG-E-MSCV-Cre)を、小脳外側核へアデノ随伴ウイルスベクター(AAV-DJ-EF1-DIO-hM4D(Gi)-mCherry)を投与し、脳内出血に続く麻痺側上肢集中使用（リハビリテーション）前後にペレットリーチングによる上肢機能を評価した。その結果、出血後のリハビリテーションにより12日後に改善を示した上肢機能が、CNO投与によりその改善効果が消失することが明らかになった。CNO作用は投与3時間後には消失することも確認した。以上より、CNO投与による小脳-赤核路の選択的神経遮断によって、脳出血後の麻痺側集中使用による上肢機能の改善が有意に消失することが示された。 小脳外側核刺激による赤核での電気応答変化の確認では、多点電極ローブを用い小脳外側核を電気刺激し、赤核小細胞部から得られた集合電位を計測評価した。これまでに個体数は生食投与コントロール群およびCNO投与群ともにn=1であるが、小脳外側核刺激に応答する集合電位は生食投与１時間後まで大きな変化がないのに対し、CNO投与群では投与20分以降に最大３５％程度の電位の減少が確認された。今後n数を増やす必要はあるが、CNO投与による小脳-赤核路の神経遮断効果の電気生理学的な傍証が推測される。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2018/04 -2022/03 
    Author : TAJIRI NAOKI
     
    Hypoxia-ischemia (H-I) in preterm infants occasionally results in neonatal white matter injury (NWMI) associated with neurodevelopmental disabilities such as paralysis and cognitive dysfunction. To find out new effective treatment for NWMI, we are challenging cell therapy to NWMI model using oligodendrocyte progenitor cells (OPCs) as well as focusing on the enriched environment (EE). In study 1, we investigated whether the grafted OPCs can promote motor function in NWMI model via immunosuppressant. In study 2, we examined whether EE could improve the motor dysfunction caused by NWMI, and change the microenvironment. Our data suggest that OPC transplantation during the period of development has a potency to improve deteriorated motor function and increased cell survival and cell differentiation rate of grafted cells in the NWMI model. Also, we clarified that long-term EE rearing in NWMI model, is one of treatments that can promote brain development.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2018/04 -2022/03 
    Author : Hida Hideki
     
    Our final purpose is the establishment of cell therapy to perinatal white matter injury (PWMI). To establish cell therapy to a PWMI model rat using oligodendrocyte progenitor (OPC), we revealed that grafted OPC survived in the corpus callosum (CC) until 8week after the graft, and IGF-2 that is upregulated in the model brain exhibited trophic effect on cultured OPCs. Furthermore, to analyze the mechanism of the survival of the grafted cells in the CC, we performed several experiments focusing on the relationship between myelination and the recovery of the disturbed function: the analysis of myelin formation by FRET following to the construction of in vitro myelination system, and the analysis of the effect of environmental enrichment during the period of the development on the PWMI model.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2020/03 
    Author : Misumi Sachiyo
     
    The effects of insulin-like growth factor type (IGF-2), which expression is enhanced in the brain of neonatal white matter injury (NWMI), on differentiation of oligodendrocyte progenitor cells (OPCs) in vitro and on the ability of OPCs to differentiate in vivo were investigated, aiming to clarify the mechanism of differentiation of grafted OPCs from overcoming inhibitory action of the brain in a NWMI model. We revealed that the treatment of IGF-2 alone can induce to differentiate OPCs to mature oligodendrocytes. We also reported that overcoming inhibitory effect in the brain of NWMI is rather important than trophic effect by IGF-2 to promote maturation of grafted OPCs in vivo: less number of grafted OPCs were differentiated to CC-1-positive mature OLs in a NWMI model compared to sham-operated control.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2020/03 
    Author : Hamaguchi Yasuyo
     
    The purpose of this investigation was to study the pro-social behavior of students majoring in medical studies. We used an experimental economics method to compare the decision making styles of medical school students and those of non-medical students. It was very hard to recruit many subjects from different faculties because of administrative barriers. Because of this research fund, we could introduce ORSEE (known as a reliable experiment recruitment system) in our university for the first time and could recruit many subjects successfully.Unfortunately, we had to cancel some experiment sessions in March because of COVID-19. Therefore, we could not collect enough data as we planned.
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2017/04 -2019/03 
    Author : 飛田 秀樹
     
    脳血管障害による運動機能障害の軽減には集中的なリハビリテーション（以下リハ）が重要である。集中的なリハは残存した神経回路の再編成を介して運動機能の再獲得を促進すると考えられているが、どの回路が、どのタイミングで関わるのかといった詳細な作用機序については不明な点が多い。 本研究では、内包出血モデルラットに対して麻痺側前肢の集中使用を課し、それによる皮質-脳幹回路の変化および機能回復との因果性を検証した。これまでの検討により、リハによる機能回復には皮質赤核路が重要であること、皮質赤核路を遮断してリハを行うと皮質網様体路において豊富な軸索分枝を生じること等が示されている。本年度は、皮質赤核路および皮質網様体路に対しウイルスベクターを予め感染させ両経路を選択的に機能遮断できる系を用い、運動機能との関連性を検証した。 結果として、皮質赤核路を遮断しリハを行い、その後皮質網様体路の選択的な抑制を行うと、改善した運動機能が低下することが示された。これは皮質赤核路遮断により生じた皮質網様体路の賦活化が運動機能回復と関連を有することを証明するものである。更に、リハ終了後に皮質赤核路を遮断すると改善した運動機能が低下するものの遮断を維持すると運動機能が徐々に改善してくる。この時点で皮質網様体路を遮断すると、運動機能が再度低下することが示された。 これらの結果は、皮質赤核路が遮断されると皮質網様体路へのダイナミックなスイッチングが生じ、この現象がリハによる運動機能の回復と密に関わることを示唆するものであり、脳血管障害後のリハにおける神経回路レベルでの作用機序の一端を詳らかにするものであると考える。本年度においては更にウイルスベクター感染に関する電気生理学的および組織学的証明を加え、海外誌(J. Neuroscience)に投稿を行い、現在revise中で近く受理される見込みである。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2015/04 -2019/03 
    Author : Suzuki Motohiko
     
    siRNA (smalll interfering RNA) can inhibit gene expression specifically. In this study, we showed that antigen-specific regulatory T cells can be induced by CD40 siRNA (siRNA against CD40)-transfected antigen-pulsed dendritic cell in vitro. We also demonstrated regulatory T cells induced by CD40 siRNA-transfected antigen-pulsed dendritic cell inhibited antigen-specific IgE in sera, eosinophilia in nasal mucosa, allergic nasal symptom (the number of sneezes and nasal rub movements) in mice with allergic rhinitis.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2015/08 -2017/03 
    Author : UEDA Yoshitomo; ISHIDA Akimasa; HIDA Hideki
     
    Rehabilitation by constraint induced movement therapy (CIMT) improves performance of injured upper limb. To reveal the involvement of midbrain-cortex dopamine pathway, which relates to motivation, in CIMT, we attempted to selectively block ventral tegmental area (VTA) - motor cortex (M1) pathway using two kinds of virus vectors. Obvious result of virus vector infection was not obtained until now. The problem could caused by handling errors of virus vectors and/or manipulation errors of virus injection to the brain. Moreover, we should reconsider the structure of virus vectors and injection sites and number of times. Experimental setup was already prepared, so we continue these trials.
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2015/04 -2017/03 
    Author : 飛田 秀樹
     
    脳血管障害後の有効なリハビリ法に、麻痺側上肢を集中的に使用させるCIMT療法がある。CIMTによる早期からの上肢機能の回復が、皮質赤核路の促通性亢進による直接的作用によるのか？他の神経回路を介する間接的作用によるのか？について、解析を進めた。具体的には、脳出血前に予め二重ウイルスベクター感染法により赤核へレンチウイルスを運動野へアデノ随伴ウイルスを感染させ、CIMT後に皮質赤核路をドキシサイクリン(DOX)投与で選択神経遮断する時期を可変化させ、上肢機能を評価した。一方、赤核における促通性亢進関連因子の探索も行った。 これまでに、脳出血作成前にレンチウイルスおよびアデノ随伴ウイルスを感染させ、１. CIMT開始期（出血１日後）からのDOX投与による持続的な神経遮断、２. CIMT終了5日後（出血13日後）からの皮質赤核路の神経遮断、を実施し、上肢運動機能の評価を行った。その結果、CIMT開始期から皮質赤核路を選択遮断した場合には、出血１～８日後の１週間のCIMTにより上肢機能の改善が観察された。このとき、皮質赤核路の神経投射の増加は認められないのに対し皮質網様体路の網様体部への神経投射が多く認められることが明らかになってきた。一方、CIMT終了5日後の出血13日後からの７日間を神経遮断した場合には、遮断直前（出血12日後）に確認されたCIMTによる上肢機能改善がDOX投与により完全に消失した。すなわち、出血後早期のCIMTにより皮質赤核路が早期からの機能回復に重要であることが明確になった。また同時に、早期CIMT中の皮質赤核路の神経遮断は、皮質網様体路を含む他の神経回路による機能回復メカニズムを誘引することも示唆される。 一方、赤核の促通性亢進関連因子の探索は、脳出血後のCIMTで発現増加する成長関連因子などを網羅的に調べ、いくつかの候補遺伝子を明らかにした。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2014/04 -2017/03 
    Author : HIDA HIDEKI; MISUMI SACHIYO; ISHIDA AKIMASA
     
    Using spontaneously hypertensive rat, the change of emotional behavior by monosodium glutamate (MSG) intake during the period of development was investigated. MSG ingestion resulted in a significant reduction in aggressive behavior. To know the mechanism in less aggression, several experiments were performed as follows. Blood pressure was comparable to the controls. Argyrophil III staining to detect neuronal damage revealed no evidence of injury in the aggression-related brain areas. Assessment of plasma amino acids revealed a transient increase of the ingestion after fasting. However, lactate dehydrogenase assay in blood–brain barrier in vitro model showed that cell toxicity was not induced by indirect MSG application even at 700 microM. The vagotomy at sub-diaphragm level indicated that aggressive behavior is mediated by vagus nerve. Data suggest that MSG ingestion during the period of development could reduce aggressive behavior, mediated by gut-brain interaction.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2017/03 
    Author : HAMAJIMA Yuki
     
    Olfactory mucosa autografts transplantation has been shown to improve the outcome after spinal cord injury. Olfactory mucosa contain neural stem cells, called olfactory stem cells (OSCs), which produce broad trophic support required for promoting axonal regeneration. The OSCs were isolated from the olfactory mucosae of newborn mice and expressed the neural stem cell markers, Nestin, Musashi-1, Nanog, and Sox-2. When differentiated, the OSCs expressed bIII-tubulin, GalC and GFAP, confirming the multipotency of the OSC. The OSCs secreted nerve growth factor and several cytokines that can promote nerve regeneration. In this study, Medgel, a biodegradable hydrogel sponge, was applied to place OSCs around the transplanted site and to avoid the local hostile environment. When OSCs were transplanted after facial nerve injury, accelerated recovery was observed for one week. When OSCs were transplanted with Medgel, a higher level of accelerated recovery was observed throughout the study.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2016/03 
    Author : Murakami Shingo; Hida Hideki; Hamajima Yuki; Esaki Shinichi
     
    Bell’s palsy is highly associated with diabetes mellitus (DM). Diabetes mellitus was induced with streptozotocin injection in only mice that developed transient facial nerve paralysis with HSV-1. Recurrent facial palsy was induced after HSV-1 reactivation by auricular scratch. After DM induction, the number of CD3+ T cells decreased by 70% in the DM mice, and facial nerve palsy recurred in 13% of the DM mice. HSV-1 DNA was detected in the facial nerve of all of the DM mice with palsy, and HSV-1 capsids were found in the geniculate ganglion using electron microscopy. These results suggested that HSV-1 reactivation in the geniculate ganglion may be the main causative factor of the increased incidence of facial paralysis in DM patients.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2012/04 -2015/03 
    Author : NAKAYAMA Meihou; HIDA Hideki; SUZUKI Motohiko; KURIYAMA Shinichi
     
    Our gorals are, creating nasal allergic mice, observing neuron cells damage of hippocampus by argyophil III stain, and measuring sleep brain wave to compare how do nasal allergy mice affect their hippocampus, and their sleep quality. After the first step, new anti-allergic medicine CD40 created by Motohiko Suzuki will inject to all mice, to observe if the medication may improve their allergy as well as their sleep quality, also assist neuron cells function in hippocampus. At this moment, several experiment regarding effectiveness on CD40 to mice nasal allergy already done by our teams. In our future works, once this subject is completed, this CD40 may be possible using to human to help how are suffered with nasal allergy and sleep disorders. Since insomnia has been reported that may affect human memory, this project may also help neuron cells in brain.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2012/04 -2015/03 
    Author : SUZUKI MOTOHIKO; NAKAYAMA Meihou; NAKAMURA Yoshihisa
     
    Gene silencing using small interfering RNA (siRNA) is a potent, selective, and widely-applicable method for specifically blocking expression of desired genes. Small interfering RNA is more attractive due to its high specificity, as well as superior potency when compared to antisense oligonucleotides. Intranasal administration of CD40 siRNA expressing vector (CD40 shRNA) significantly inhibited the number of sneezing and nasal rubbing in mice with allergic rhinitis. Intranasal administration of CD40 siRNA also inhibited the number of sneezing and nasal rubbing in mice with allergic rhinitis. Also, intranasal administration of siRNA specific for IL-5 also inhibited the number of sneezing and nasal rubbing in mice with allergic rhinitis.
  • 注意欠陥多動性障害モデル動物での豊かな環境飼育による脳内ドパミン神経系の変化
    Date (from‐to) : 2012 -2014 
    Author : 飛田秀樹
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2010 -2012 
    Author : HAMAJIMA Yuki; HIDA Hideki
     
    Many tissue-drived stem cells existed in the Olfactoy fissure of the fetus mouse, cultured that tissue-drived stem cell, transplanted around the facial nerve of the facial nervous paralysis model mouse. As a result, by comparison with the model mouse which heals naturally by transplanting the organizational tissue-drived stem cell of olfactory mucous membrane origin around the paralysis nerve in the facial nervous paralysis model mouse, it was suggested that the period when it requires for facial nervous paralysis improvement is shortened significantly. Concerning paralysis improvement, with the tissue-drived stem cell transplantation mouse and the natural healing group significant difference was not recognized in both groups. Concerning the playback of the nerve, the fact that nervous playback is active is shown, it could recognize the taking in BrdU mainly. Neural stem cells from olfactory mucosa may recover mouse facial nerve palsy better.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2010 -2012 
    Author : MURAKAMI Shingo; HAMAJIMA Yuki; HIDA Hideki
     
    Hepatocyte growth factor (HGF) has been reported to accelerate recovery in central nerve system, but its function in peripheral nerve system is unclear. We transfected HGF using replication-defective herpes simplex virus vector into crushed facial nerve. Recovery from facial nerve palsy was accelerated clinically, electrophysiologically, and pathologically. Transfected cells were detected using immunohistochemicalstaining.Close relationship between HSV and sudden deafness or vestibular neuritis has been reported. We inject HSV-1 or HSV-2 into tympanic cavity of mice. Vertigo and hearing loss was observed in those mice. HSV-infected, apoptotic cells were found in stria vascularis; however, apoptotic cells found around Corti’s organ was not infected with HSV. Apoptosis induction after HSV infection differed according cell types.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2009 -2011 
    Author : SUZUKI Motohiko; HIDA Hideki
     
    We previously reported that systemic administration of CD40 siRNA attenuated allergic symptoms. However, this is an allergen-nonspecific fashion. Therefore, we tried to develop a new allergen-specific therapy for allergy using CD40-silenced and allergen-pulsed dendritic cells(DCs). Bone marrow-derived DCs were transfected with CD40 siRNA and pulsed with ovalbumin(OVA). Mice were sensitized intraperitoneally with OVA and keyhole limpet hemocyanin, followed by intranasal challenge with these allergens. Mice were treated with CD40-silenced and OVA-pulsed DCs(CD40-silenced OVA DCs) before allergic sensitization. The mice receiving CD40-silenced OVA DCs inhibited allergic symptoms caused by OVA challenge, as well as anti-OVA IgE levels in sera. Also, CD40-silenced OVA DCs suppressed eosinophil infiltration at the nasal septum, OVA-specific T-cell responses, and T-cell production of IL-4 and IL-5 after stimulation with OVA. However, CD40-silenced OVA DCs did not inhibit keyhole limpet hemocyanin-induced allergy, suggesting that CD40-silenced OVA DCs induce allergen-specific tolerance. I reported that dendritic cells, which were transfected with CD40 siRNA and pulsed with ovalbumin(OVA), inhibited allergic rhinitis induced by OVA antigen but not the other antigens, suggesting that this is antigen-specific therapy.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2009 -2011 
    Author : MIZUNO Keisuke; HIDA Hideki; MASUDA Tadashi; MISUMI Sachiyo
     
    It was revealed by the assessment of motor functions(rotarrod, motor deficit score and cylinder test) that a rat model of periventricular leukomalasia(PVL) is appropriate to the model for a longer time. It became possible to induce oligodendrocytes and its progenitors(OPC) from mouse ES cells/iPS cells in vitro as the donor cells to PVL. In transplantation of iPS cells-derived OPC to PVL model rat, grafted cells can survive well in the white matter, revealing that some substances such as trophic factors will be needed for better survival rate.
  • 豊かな環境飼育による中脳皮質辺縁ドパミン神経系の活性化と栄養因子の関連性の解析
    Date (from‐to) : 2008 -2011 
    Author : 飛田秀樹
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2008 -2010 
    Author : ISOBE Yoshiaki; NAKANISHI Makoto; HIDA Hideki
     
    Two self-oscillating systems are running in vertebrate organ that are circadian rhythm and cell cycle. Proliferating neurosphere was prepared from the dispersed cell culture of preoptic neuroepitherium in E14 rat fetus brain. After the second passage, the cells were collected 6 hr intervals at 9:00, 15:00, 21:00 and 03:00. Proportion of G1cells at 9:00 was smaller than that at 21:00. Per2 and p27 mRNAs showed similar circadian rhythms, which peaked at 21:00. From the results, cell cycle is tightly controlled by the component of circadian rhythm.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2007 -2008 
    Author : HAMAJIMA Yuki; HIDA Hideki
     
    胎児マウス嗅上皮粘膜より、組織幹細胞を取り出した。浮遊細胞は球状なneuro-sphere を形成し、12ヶ月以上継代することが出来た。マウス骨髄からも同様にsphereを形成する培養細胞が分離できたが、2ヶ月程すると、細胞はアポトーシスを起こし、消失していったのに対し、鼻粘膜由来の細胞は15ヶ月継代することができた。これらの細胞からRNA を抽出し、RT-PCRにて神経系マーカーの発現をみると、Musashi1、Nestin、などの神経幹細胞を示唆する遺伝子の発現を認めた
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2007 -2008 
    Author : MURAKAMI Shingo; HAMAJIMA Yuki; NAKAJIMA Katuhisa; HIDA Hideki
     
    HGF を弱毒化したHSV ベクターで遺伝子導入することにより末梢神経再生を促進できることが判明した。しかし、ウイルス性顔面神経麻痺モデルマウスの神経再生は促進できなかった。しかし、フリーラジカルスカベンジャーにより、顔面神経麻痺の治療効果が期待できることが判明した。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2005 -2006 
    Author : OZEKI Masashi; HIDA Hideki; HAMAJIMA Yuki
     
    Inhibitors of differentiation (Id) play an essential role in the neurogenesis of the central nervous system. However, the expression and function of Id in the development of cochlear sensory epithelial cells have yet to be elucidated. In this study, we demonstrate the Id1 gene was expressed in the rapidly growing otocyst on embryonic day 12 (E12) and in the organ of Corti, spiral ganglions, and stria vascularis on postnatal day 1 (P1) by cellular and molecular biologic techniques. Knockdown of the Id1 gene with short interfering RNA (siRNA) in a cochlear sensory epithelial cell line (OC1) significantly reduced its proliferation, whereas overexpression of Id1 in OC1 significantly increased the proliferation of OC1, suggesting a role of Id1 in the development of cochlear sensory epithelial cells. The proliferative action of Id1 on OC1 was mediated by nuclear factor-kappaB (NF-kappaB) and cyclin D1 (a downstream molecule of NF-kappaB). Blockage of the NF-kappaB activity with pyrrolidine dithiocarbamate (PDTC) or enhancement of the NF-kappaB activity with p65 (a subunit of NF-kappaB) in OC1 significantly inhibited or increased, respectively, the cell proliferation and transcription of cyclin D1 induced by Id1. Truncation of the NF-kappaB binding site in the cyclin D1 promoter fully abrogated the transcription of cyclin D1, suggesting that the cyclin D1 transcription is dependent on NF-kappaB. We concluded from this study that Id1 induces the proliferation of OC1 via the NF-kappaB/cyclin D1 pathway.
  • 神経幹細胞の栄養因子による神経分化誘導と分化機構の解明による障害脳機能の再建
    Date (from‐to) : 2004 -2006 
    Author : 飛田秀樹
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2003 -2005 
    Author : NISHINO Hitoo; MIURA Yutaka; HIDA Hideki
     
    Neural stem cells (NSCs) are self-renewing and multi-potent, thus are reasonable candidates of donor cells for neural transplantation once they steadily directed to neurons. In the present study, differentiation from NSCs to DAergic neurons and their application to reconstruction medicine were investigated. NSCs developed mostly to astrocytes in an ordinary culture system with serum. However, majority (over 80%) of ES cells-derived NSCs could be developed to neurons using 5 steps culture protocol with cytokines and trophic factors. Micro-array analysis revealed many genes were up-regulated or down-regulated in association with differentiation to neurons from NSCs. Among them, pleiotrophin highly expressed in NSCs showed a strong trophic and survival effects on DAergic neurons and progenitors. In embryonic brains, a homeotic factor ATBF1 was expressed in cells located in differentiation zone coexpressing with β- tubulin and MAP2. In expression study of neuroepithelial cells, Neuro 2A cells and P19 cells, it was found that when ATBF1 was expressed in cytosole cells proliferated continuously, and when ATBF1 was expressed inside nucleus cells left cell cycle and differentiated to neurons. Intra-nuclear transport of ATBF1 was dependent on the activity of PI(3) K-kinase and extranuclear (cytosol) localization was CRM1dependent. Thus, a homeotic factor ATBF1 was found be involved in neuronal differentiation, brain development, formation of brain architecture and so on. Results of the present study would be applied to various fields such as neural differentiation, reconstruction medicine, brain development and education.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2003 -2004 
    Author : OZEKI Masashi; HIDA Hideki
     
    Cochlear progenitor hair cell line are useful for studies of cellular specification, gene expression features, and signal transduction involved in development of hair cells. To obtain embryonic and postnatal cochlear progenitor hair cell lines, we immortalized primary cultures of sensorineural epitherial cells from otocysts on embryonic day 12(E12) and explants of organ of Corti tissues on postnatal day 5(P5). Primary cultures and explants were then tranduced by thr E6/E7 genes of human papilloma virus type 16, and were passed for > 50 passages and partial clonal cells were isolated by limiting dilution. The expression of neuronal, neural, epithelial, hair cell markers and important transcription factors were examined in these cell lines. These cell lines may represent progeniotor hair cells at the different stages of cochlear development. Another result is as described below. Inhibitor of differentiation (Id3) is an important transcription factor expressed in the cochlear tissue and progenitor hair cells. It is likely to be involved in cell-cycle progression and the proliferation of cochlear progenitor hair cells during the embryonic stage. To characterize the expression of Id3 in the developing cochlear tissue and explore its role in the growth and proliferation of progenitor hair cells, the expression of Id3 gene in the developing cochlear tissue was examined by means of molecular biological methods and progenitor hair cell line were studied using specific antisense oligonucleotides. The Id3 gene was expressed in the rapidly growing otocyst on embryonic day 12 and specifically in the fundamental structures of the cochlea, e.g. the organ of Corti, spiral ganglions and steria vasclaris, on postnatal day 1. Inhibition of Id3 gene expression with antisense oligonucleotides in cultured otocyst epithelial cells and OT 12p reduced DNA synthesis and cell-cycle progression, suggesting that Id3 participates in the proliferation of cochlear progenitor hair cells.
  • 脳内出血に対する神経幹(前駆)細胞移植による脳機能の再建のための基礎的研究
    Date (from‐to) : 2002 -2003 
    Author : 飛田秀樹
  • オリゴデンドロサイトにおける内向き整流性カリウムチャネルの制御と細胞死との関連
    Date (from‐to) : 1999 -2000 
    Author : 飛田秀樹
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1998 -1999 
    Author : NISHINO Hitoo; INUBUSHI Toshiro; FUKUDA Atsuo; HIDA Hideki; MORIKAWA Shigehiro; BORLONGAN Cesario v.
     
    Systemic administration of 3-nitropropionic acid (3-NPA, 20 mg/kg, s.c., daily, 2 or 3 days) to rats induced striatum selective lesions, and animals manifested motor symptoms. In the present study, we analyzed the mechanisms of the striatal vulnerability and tried to protect the damage. Results are as follows. 1. 3-NPA intoxication induces the depletion of ATP thus leading to the depolarization of the cell membrane and release of glutamate. The depolarization and the excess amount of glutamate induce neuronal cell death in the center of the striatum. 2. The depolarization also induces the excess release of dopamine (DA) that leads to neuronal and astroglial cell death in the lateral striatum. 3. A very early state of neuronal damage was detected by argyrophil III silver impregnation. 4. Estrogen protected against while testosterone exacerbated the striatal lesions induced by 3-NPA. 5. Fetal striatal cells were transplanted into the injured striatum one month after 3-NPA intoxication. Once the cells survived, they extended neurites into the host striatum and resulted in the improvement of the motor symptom. 6. After 3-NPA application in vitro, astrocytes were more sensitive than neurons in the increase of [CaィイD1++ィエD1]ィイD2iィエD2, and they got into necrotic cell death. 7. bFGF, thrombin and melatonin protected in vitro astrocytic cell death induced by the application of 3-NPA, sodium nitroprusside (NO donor) or serum-free medium.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1997 -1999 
    Author : NISHINO Hitoo; TORII Kunio; HIDA Hideki; AGUI Takashi; FUKUDA Atsuo
     
    We first developed Huntington's model rats by systemic administration of 3-nitropropionic acid (3-NPA) and then tried to protect the symptoms using antisense strategy. 1. Acute intoxication with 3-NPA induced acute brain symptoms and resulted in the damage of the BBB and necrotic cell death of the striatum, while chronic intoxication resulted in hypotonic paralysis in lower extremities with motor disturbances. 2. The dysfunction of the BBB localized to the centrolateral striatum with the damage in endothelial cells and astrocytes of the lateral striatal artery. 3. The mechanism of the specific vulnerability of the lateral striatal artery (the dysfunction of the BBB) is summarized as follows i) The angle of branching is sharp in this artery, thus easy to make turbulent flow at the bifurcation and make damage in endothelial cells. ii) The metabolism of nitric oxide (NO) in this artery is set at a higher level : the expression of eNOS message and the production of NOx are extensive. iii) Astrocytic end-feet uptake actively 3-NPA, having a similar structure as glutamate, through their glutamate-transporter, and the astrocytes fell into necrosis faster than neurons. 4. Co-injection of 3-NPA and an inhibitor of the glutamate-transporter reduced the astrocytic cell death in the striatum. 5. Application of the antisense of GLAST (glutamate-transporter) in the lateral ventricle increased the level of NOx in the striatum and worsened the motor symptoms. 6. More localized application of the antisense in the lateral striatum will improve the symptom or not should be investigated in future study.

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