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UEKI Takatoshi

    Graduate School of Medical Sciences Department of Integrative Anatomy　Professor
Last Updated :2024/04/24

Researcher Information

URL

J-Global ID

Research Interests

  • 包括脳ネットワーク   神経幹細胞   神経細胞死   虚血   骨形成因子   Fra-2   EGF   幹細胞療法   PD98059   in vivoイメージング   PET   神経新生   ギャップ結合   bFGF   MAPキナーゼ   connexin-43   精神・神経疾患   アストロサイト   

Research Areas

  • Life sciences / Anatomy
  • Life sciences / Metabolism and endocrinology
  • Life sciences / Basic brain sciences
  • Life sciences / Neuroscience - general / Clinical Neuroscience

Academic & Professional Experience

  • 2009 - 2013  Hamamatsu UniversitySchool of Medicine Department of Anatomy and NeuroscienceAssociate Professor

Published Papers

MISC

Research Grants & Projects

  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2021/04 -2026/03 
    Author : 杉浦 健之; 太田 晴子; 近藤 真前; 酒井 美枝; 藤掛 数馬; 仙頭 佳起; 植木 美乃; 植木 孝俊
     
    本研究では、体性感覚や内受容感覚に注意が向いている際に現れる脳血流量の変化を指標とした脳機能検査の確立を目的としている。痛み感覚・体性感覚検査として、定量的感覚検査が適切であるか、脊髄のwind-up現象のような痛みの伝導増強機能を評価するとされるtemporal summation(TS)、下行性疼痛制御機能を評価するとされるcentral pain modulation(CPM)の評価を行なった。16名の健常人で、繰り返しの刺激で痛みの強度（VAS）が増加したものは75%（12名, VAS+12~＋145 %）、痛み負荷条件（VAS>60, 11名）のうち、痛み強度の軽減が確認できたものは、36％（４例, VAS-3~-39 %）であった。 研究結果に与える影響を調査するため、外来を受診した慢性疼痛患者の検査結果を評価した。ICD-11で一次性慢性痛に分類された患者は61人(①慢性一次性筋骨格系痛（n=27）が最も多く、②慢性一次性全身痛（n=17）、③慢性一次性頭痛・顔面痛（n=16）、慢性一次性内臓痛（n=1）)であった。患者特性に関して、慢性一次性全身痛では、日常生活での不自由度、不安・抑うつスコアーが他に比べて高く、頭痛・顔面痛では、痛み強度と痛みに対する破局化思考が高い傾向にあった。精神科医の診察で、一次性慢性痛の約6割の患者（61人中、37人）に、何らかの精神疾患（うつ病、双極性障害、身体症状症など）や発達障害（ADHD、ASD）が診断されたことは重要な知見である。一方、二次性慢性痛では、2割の患者（44人中、10人）にしか、精神疾患や発達障害は診断されなかった。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2019/04 -2023/03 
    Author : 石田 和人; 植木 孝俊; 松下 光次郎
     
    本研究課題における昨年度の取り組みにおいて、高脂肪食の継続的投与により、実験動物（マウス）が、抑うつ様行動を示すようになることを確認した。さらに今年度は、脳卒中後うつに着目したリハビリテーションの効果についても、検討を加えることを着想し、高脂肪食投与後、脳出血を引き起こすことで、脳卒中後うつマウスモデルの確立を目指すこととした。しかし、先行研究では、脳内にコナゲナーゼを微量注入して作成された脳出血マウスにおいて、4週間ほど経過するのみで、抑うつ様行動を呈することが報告されていたため、今年度の第一段階として、脳出血マウスの作成を試み、本モデルが抑うつ様行動を示すか否かについて検討することとした。その結果、マウスによっては、典型的な運動麻痺の様相を呈する脳出血マウスを作成することができたが、十分な運動麻痺を惹起させられないマウスもあり、障害程度がばらつく結果であった。今後、検討を重ねて、再現性の高い脳卒中モデルを作成するとともに、それ自体により、抑うつ様行動を示すか否かを、まず自験例で確認したい。さらには、昨年度、検討した継続的な高脂肪食投与と脳出血マウス作成を併用することにより、脳卒中後うつモデルが作成できるかどうかを検討し、同モデルに対するリハビリテーションの効果を検討したい。肥満、脂質代謝異常、インスリン抵抗性など、いわゆる生活習慣病の因子を加えて検討することにより、実際にヒトで生じている抑うつの病態にせまる検討が可能となるものと考える。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2019/06 -2022/03 
    Author : Sato Kohji
     
    The involvement of adult neurogenesis in the pathophysiology of psychiatric disorders such as major depression and schizophrenia has recently reported. The necessity of technology for in vivo imaging of adult neurogenesis in the brain is deeply recognized in early diagnosis of those kinds of incurable mental diseases, however, the technology has not established to date. In this study, PET imaging system based on newly synthesized chemical compound and its derivative PET trace, which specifically binds to CD133, expressing on the cellular membrane of neural stem cell, was established. By this PET imaging system, the dynamism of adult neurogenesis in the brain of major depression model mouse was clearly visualized in the living animal.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2018/04 -2022/03 
    Author : Sakuma Eisuke
     
    We aimed to test the hypothesis that ASIC2a mRNA expression might correlate to the morphological development of the cerebellum. To that end, we examined the development of cerebellar cortex in the rats from embryonal day 15 to 14 day-old after birth compared with 28-day and 2-years old rats’ cerebellums focusing on the ASIC2a mRNA expression by using in situ detection of ASIC2a mRNA transcription using the RNA scope detection kit. We observed that ASIC2a expression migrates in a manner consistent with the migration of granule cells from the outer to the inner layers of the cerebellar cortex during cerebellogenesis. This suggests that ASIC2a is involved in enhancing synaptic neurotransmission when cell migration occurs during postnatal cerebellar circuit construction, and that ASIC1a is always maintained as the basis of synaptic neurotransmission.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2017/04 -2021/03 
    Author : Mikawa Sumiko
     
    In the present study magnetic resonance imaging (MRI) switching probe was newly developed to visualize in vivo under MRI the activity of pathological proteinase, ADAM10, which generates soluble fractalkine (FKN) from membrane bound form of FKN. The production of soluble FKN in the co-culture system of neuron and microglia was quantitatively analyzed according to the principle of paramagnetic relaxation, where MRI switching probe was originally designed and synthesized. And here the brain slice culture system derived from rodent model of schizophrenia was used to comprehensively analyze gene expression pattern in microglia at the onset of inflammation. As the results a series of molecules associated with the activation of microglia were identified.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2019/03 
    Author : Ueki Takatoshi
     
    In the present study the investigators aim at exploring the neuropathology underlying microglial activation in the brain in the early stage of onset of schizophrenia, and development of in vivo MRI system to visualize behavior of microglia. Here, based on the observation that processing of fractalkine in the adjacent neuronal axon triggers microglial activation via its membranous CRXCR3 receptor, the pathophysiology of the activation of metabolic enzyme of neuronal fractalkine was explored and also MRI switching molecular probe to visualize the enzymatic activity was developed.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2015/11 -2018/03 
    Author : IKENAKA Kazuhiro; ITO Kei; UEKI Takatoshi; OHKI Kenichi; KATO Takahiro; KANEMARU Kazunori; SHIMIZU Takeshi; TAKEBAYASHI Hirohide; TANAKA Kenji; HASHIOTO Kohichi; YAMAZAKI Yoshihiko; INOUE Kazuhide; OKABE Shigeo; OZAKI Norio; KANBA Shigenobu; KIRA Junichi; KOHSAKA Shinichi; FUKUYAMA Hidenao; BANNAI Hiroko; NAKASHIMA Kinichi; IMAI Hiroo; MATSUI Ko; TACHIKAWA Masanori; KAKEGAWA Wataru
     
    We Glia Assembly communicated with Glial Heterogeneity (sponsored by DFG, program name SPP1757, project leader Dr. Frank Kirchhoff) and organized the international research consortium, called “YoungGlia”. The purpose of this framework is to stimulate mutual exchange visits of young researchers of glial research. The collaborative research between Japan and Germany will be carried out by the young researchers.The collaboration must be approved by the principle investigators on both sides but the original proposal and execution of the research itself must be done by the young researchers. According to the above basic concept, we selected 11 research pairs at 1st (FY2015) and 2nd (FY2016) YoungGlia and supported their international collaborations for 1-2 years. We organized 3rd YoungGlia (FY2017) and all funded pairs presented their achievements. In addition, at the 3rd YoungGlia, we invited Canadian and American groups and expanded our partnership beyond Japan-Germany communication.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2015/04 -2018/03 
    Author : Sato Kohji
     
    The investigators previously found microglia is aberrantly activated in the brain of schizophrenic patients by positron emission tomography. In the present study the investigators aim at exploring the neuropathology underlying microglial activation in the brain in the early stage of onset of schizophrenia, and development of in vivo MRI system to visualize behavior of microglia. Here, based on the observation that processing of fractalkine in the adjacent neuronal axon triggers microglial activation via its membranous CRXCR3 receptor, the pathophysiology of the activation of metabolic enzyme of neuronal fractalkine was explored and also MRI switching molecular probe to visualize the enzymatic activity was developed.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/06 -2018/03 
    Author : Fukuyama Hidenao
     
    We found a lot of results on Schizophrenia, ADHD, Depression in human brain. Using molecular imaging, we also revealed microglial function in the brain to regulate reward system, as well as astrocyte interactions.Animal model for Schizophrenia showed the microglial malfunction by ADAM10 activation, and those protease functions related Schizophrenia was visualized by tracers of microglia for animal MRI.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/06 -2018/03 
    Author : Ikenaka Kazuhiro
     
    Managing Committee of Scientific Research on Innovative Area “Glial Assembly” aimed to open our achievement to the public. For this purpose we organized Open Symposia for 5 times (two of which were international symposia). Also we participated and organized two symposia in Comprehensive Brain Science Network together with other Scientific Research on Innovative Area. Through these activities we succeeded in making the concept “Glial Assembly” popular in the neuroscience community.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2014/04 -2017/03 
    Author : Yasuomi Ouchi
     
    The previous in vivo studies on microglial activity mainly described the features of inflammatory microglial activation, which did not allow detection of which was contributory to neuroinflammation in diseases, protective or inflammatory microglia. So, a new method that could monitor microglial activation using imaging technique was longed for to elucidate the contribution of microglial activation in diseases. We tried to develop a new monitoring system by MRI and PET about dynamic aspects of microglial activation, namely, development of a MR probe that depended on the amount of fractalkine produced and a PET CB2R ligand imaging for activated microglia. Although an MR probe was not satisfactory, the CB2R probe was able to depict some level of microglial activation. However, a more sensitive probe was expected for illustration of two types of activated microglia.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2014/04 -2017/03 
    Author : Yasuomi Ouchi
     
    We examined molecules that relate to microglial activation and investigated a linkage between neurogenesis and neuroinflammation using AD-like animal models (SAMP8 mice and naturally-developed demented macaque confirmed by [11C]PIB for amyloid pathology) by developing methods with which we were able to quantify the amount of neurogenesis and determine the types of microglial activation: protective or inflammatory. With the SAMP8 mice, a combination of Nestin promoter LAT4 system and [18F]dFMT enabled to illustrate the neurogenesis but the signal was small and ex vivo postmortem brain imaging was found to be necessary. Using a CB2R ligand permitted to depict microglial activation, but we found a more sensitive probe and method system necessary for examining these two phenomena in vivo in a living single animal.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2016/03 
    Author : IWATA YASUHIDE; Mori Norio; Ueki Takatoshi; Wakuda Tomoyasu; Yokokura Masamichi; Takahashi Taro
     
    In the present study magnetic resonance imaging (MRI) switching probe was newly developed to visualize in vivo under MRI the activity pathological proteinase, which generates soluble fractalkine (FKN) from membrane bound form of FKN. The production of soluble FKN in the co-culture system of neuron and microglia was quantitatively analyzed according to the principle of paramagnetic relaxation, where MRI switching probe was originally designed and synthesized. And here the brain slice culture system derived from rodent model of schizophrenia was used to comprehensively analyze gene expression pattern in microglia at the onset of inflammation. As the results a series of molecules associated with the activation of microglia were identified.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2011/04 -2014/03 
    Author : SATO Kohji; MORI Norio; MATSUZAKI Hideo; UEKI Takatoshi; NAKAMURA Kazuhiko
     
    Aberrant microglial activation was recently observed in the affected brain with schizophrenia at its early developmental stage. This observation implies the involvement of pathological activation in the pathophysiology of schizophrenia. Thus the present study aimed at the investigation of molecular machinery underlying microglial activation in the pathological condition. Firstly, mice expressing fluorescein specifically in microglia were infected with poly(I:C) and model mice of schizophrenia were established. Secondarily, newly developed fluorescent imaging probe was administrated to the established schizophrenic model mice , and the activation of Caspase-1 and subsequent IL-1beta production at early phase of inflammation were visualized in vivo under two-photon microscope.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2011/04 -2014/03 
    Author : OUCHI Yasuomi; UEKI Takatoshi; OGAWA Mikako; MAGATA Yasuhiro
     
    Because it has been shown that the degree of beta-amyloid deposition in the Alzheimer's brain does not correlate with the deterioration of cognitive function, we aimed to examine the activity of ganma-secretase that regulates the production of beta-amyloid in vivo. The MRI probe that was designed to emit signals in high-magnetic field MRI worked in the in vitro setting failed to give enough NMR signals in the in vivo measurement, suggesting that a probe with a high permeability for cells and with a large signal-emitting power would be desirable.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2011 -2013 
    Author : OUCHI Yasuomi; UEKI Takatoshi
     
    It has been reported that neural stem cells are variously changed in the process of not only normal neural growth but also neuronal degeneration occurring in neuropsychiatric disorders. Despite these findings, there was no study about the contribution of neural stem cells to the physiological and pathophysiological significance. Hence we tried to develop an in vivo monitoring system with which the dynamics of the stem cells can be visualized. Using positron emission tomography with a new gene-reporter system and amino acid transporter, we were able to make a new in vivo system for measuring live neural stem cells in vivo specifically.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2010 -2012 
    Author : IWATA Yasuhide; NAKAMURA Kazuhiko; SUZUKI Katsuaki; UEKI Takatoshi; TAKEBAYASHI Kiyokazu
     
    Evidence suggests that the degeneration of neurons, abnormal axon travelling, and activation of microglia may underpin the frontal lobe dysfunction in alcohol dependence. In this study, in order to clarify the details of the frontal lobe injury in living alcoholism patients, we recruited 10 patients with alcoholism and 10 healthy comparison subjects, and examinedtheir brain with the diffusion tensor imaging, molecular imaging for activated microglia, and glucose metabolism by positron emission tomography. We also examined the relevance of the frontal lobe function to be evaluated by cognitive psychology testing battery. Asa result, we found no significant difference between the control and patients group in any of neuroimaging findings, suggesting that further evaluations with more participants will be required.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2009 -2011 
    Author : UEKI Takatoshi; FURUKAWA Hiromu
     
    An accumulating body of evidence point to the involvement of dysfunction of adult neurogenesis in the pathophysiology of neurological and psychiatric disorders such like Parkinson's disease, major depression and schizophrenia. Recently neural stem cell is recognized as a therapeutic target of diagnosis and treatment for those diseases. In the present study, therefore, at first animal system to visualize and evaluate adult neurogenesis was established, where lentivirally infected neural stem cell expresses exogenously neutral amino acid transporter LAT4 and uptake PET tracer[ 18F] FMT. In the adult rat brain transplanted or endogenous neural stem cells were infected with lentivirus and their behavioral dynamics was analyzed in vivo under PET. In addition the effects of drug candidate chemical compounds, which act as a mitogen in vitro for neural stem cell, on adult neurogenesis were quantitatively evaluated by PET. At second, in this study the established imaging technology was applied to disease model mice of major depression or schizophrenia, in which neural stem cells in the SVZ and SGZ were infected with lentivirus to express LAT4, and subsequently the mice were subjected to in vivo analysis of motility of neural stem cells in the diseased brain and study of the onset process of adult neurogenesis dysfunction. Antidepressant or psychoactive drug were administered to those animals, and the involvement of neural stem cell in the adult brain in the pathophysiology of psychiatric disorders was investigated.
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2009 -2010 
    Author : 鈴木 勝昭; 岩田 圭子; 岩田 泰秀; 須田 史朗; 植木 孝俊; 片山 泰一; 松崎 秀夫
     
    本研究の目的は、統合失調症患者の皮膚検体から線維芽細胞を採取して継代培養したのち多能性幹細胞へと誘導し、統合失調症特異的幹細胞を作出すること、そして、神経幹細胞やドパミン神経へと分化させ、その動態を調査することで統合失調症の『神経幹細胞機能不全仮説』を検証することにある。平成22年度における進捗を以下に示す。 【対象の選定】DSM-IV-TRの診断基準に基づき統合失調症と診断され、浜松医科大学附属病院精神神経科外来を受診中の成人患者を対象に、研究の目的と方法、予想される結果について患者本人及び保護者に書面を用いて説明し研究への協力を求めた。平成22年3月末の時点でも、患者本人と保護者の両者から同意が得られたケースがなく、残念ながら皮膚検体採取に至っていない。今後、引き続き研究への協力を募る予定である。 【iPS細胞からセロトニン神経への誘導】統合失調症の病態生理にあずかるセロトニン神経系の関与とその分子基盤を明らかにするためには、統合失調症患者由来iPS細胞よりセロトニン神経を調製し、その機能障害を検討することが一つの方法として考えられる。しかし、iPS細胞または胚性幹細胞からセロトニン神経へと分化させる技術はいまだ確立されていない。そこで、平成22年度は、マウス線維芽細胞よりiPS細胞を得た後に、それをセロトニン神経に分化させる方法を検討した。BALB/cマウス胎仔脳軟膜由来の線維芽細胞に、常法によりOct3/4、Sox2、Klf4をそれぞれ発現するよう調製したレトロウイルスを感染させ、LIF添加培地においてiPS細胞を樹立した。ついで、マウスiPS細胞を独自の間質細胞上に播種し、その2週間後に得られた神経幹細胞塊を分離、さらに、ShhとFGF8添加培地中で1週間培養を続けたものに、リポフェクション法によりLmxlbを強制発現させたところ、セロトニンの産生が認められ、セロトニン神経への分化が確認された。本研究の結果から、マウスiPS細胞からセロトニン神経への分化誘導が十分可能であることが示唆される。この技術をヒトiPS細胞で試みることにより、統合失調症患者皮膚由来のiPS細胞からのセロトニン神経作製が可能となることが推測される。今後、セロトニン神経の一層効率的な分化誘導を行うために、セロトニン神経のマーカーであるPet1の発現をさらに高める方法を検討する必要があると考えられた。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2008 -2010 
    Author : MATSUZAKI Hideo; IWATA Yasuhide; NAKAMURA Kazuhiko; SUDA Shiro; UEKI Takatoshi; IWATA Keiko
     
    In this study, we tried to generate recombinant retrovirus or lentivirus vector capable of nhibiting function of neuronal stem cell (NSC) to assess the role of hippocampal neurogenesis in social recognition behavior of non-human primates. This virus vector system may be useful for neurogenesis research as novel tool for NSC-specific gene expression and imaging in vivo.
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2001 -2002 
    Author : 植木 孝俊
     
    近年アストロサイトが外傷や低酸素負荷などのストレスに反応し、種々のサイトカイン等を産生することや、損傷脳においてギャップ結合の透過性に変化がみられることが報告されているが、ギャリップ結合の透過性と遺伝子発現を調節する分子機構は未だ明らかでなかった。本研究では、ギャップ結合蛋白の遺伝子発現を調節する分子機構、さらにはリン酸化等によりギャップ結合の透過性を調節する因子を同定することにより、アストロサイトのギャップ結合を介する情報伝達の意義を明らかにすることを目的とした。 申請者はこれまでに、アストロサイトのギャップ結合を構成するconnexin-43(Cx43)タンパク質の細胞内領域にMAPKによる特異的リン酸化部位があることを見出し、bFGFやEGFなどの増殖因子がMAPKの活性化によりCx43のCa^<2+>透過性を減少させることを、Ca^<2+>蛍光指示薬の一つであるFra-2を用い明らかにした。また、これらの増殖因子は、MAPKの活性化を介して、Cx43遺伝子の転写を抑制し、アストロサイトにおけるCx43タンパク質の発現を低減することを、MAPKの阻害剤をアストロサイトに投与することにより示した。 BFGF及びEGFはアストロサイトの増殖を促進するとともに、原形質性アストロサイトから線維性アストロサイトへの形態変化をもたらす。今回申請者により、増殖因子がMAPKの活性化を介してギャップ結合の発現を低減することが示されたが、ギャップ結合の発現の抑制はアストロサイト間の細胞接着を解消する一因となり、C6等のグリオーマ脳腫瘍細胞株では、ギャツプ結合の発現が低減していることが報告されていることから、筆者の研究が今後脳腫瘍細胞の増殖抑制研究の端緒となることが期待される。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2000 -2002 
    Author : SATO Kohji; WATANABE Kazuo; UEKI Takatoshi; OHNO Koji
     
    In order to prevent people from neurnal diseases, such as brain vascular diseases and Alzheimer disease, it is needed to analyze the mechanisms of neuronal cell death in detail. However, it is well known that there are different aspects in neuronal cell death depending on the causes and where it happens. In this study, using various animal models, we tried to elucidate the mechanisms of various neuronal cell death. First, using a gerbil 3-min ischemic model, we revealed that protective effect of prosaposin-derived 18-mer peptide on slowly progressive neuronal degeneration after brief ischemia. Furthermore, we succeeded to clone a new gene (Kjr). This gene codes a new protein, which can bind bone morphogenic proteins (BMP). Since the function of BMPs in the central nervous system is still unclear, this discovery may be important in this field. In addition, using in situ hybridization and immunohistochemistry, we investigated the localization of this protein, and found that this protein is expressed in astrocytes throughout the central nervous system. Especially, astrocytes in neurogenetic regions, such as the dentate grurs of the hippocampus and the subventricular zone, intensely expressed this protein. Now we are making knock out mice for this gene. Hereafter, we would like to analyze the role of this gene in ischemic conditions.

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