2021/11/29 更新

写真a

キヤマ ヒロシ
木山 博資
KIYAMA Hiroshi
所属
大学院医学系研究科 総合医学専攻 機能形態学 教授
大学院担当
大学院医学系研究科
学部担当
医学部
職名
教授
連絡先
メールアドレス

学位 2

  1. 医学博士 ( 1991年2月   大阪大学 ) 

  2. 医科学修士 ( 1984年3月   大阪大学 ) 

研究分野 4

  1. ライフサイエンス / 解剖学  / 神経解剖学 神経再生・変性

  2. ライフサイエンス / 病態神経科学

  3. ライフサイエンス / 神経形態学

  4. ライフサイエンス / 栄養学、健康科学  / 慢性疲労、慢性ストレス

現在の研究課題とSDGs 2

  1. 神経再生の分子メカニズムの解明

  2. 疲労の科学

経歴 8

  1. 名古屋大学   大学院医学系研究科、教授   教授

    2011年4月 - 現在

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    国名:日本国

  2. 名古屋大学   大学院医学系研究科、副研究科長   教授

    2017年4月 - 2022年3月

  3. 名古屋大学   教養教育院統括部(兼任)   教授

    2012年4月 - 2015年3月

  4. 大阪市立大学   名誉教授   名誉教授

    2011年4月 - 現在

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    国名:日本国

  5. 大阪市立大学   大学院医学研究科、教授   教授

    2001年1月 - 2011年3月

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    国名:日本国

  6. 旭川医科大学   医学部、教授   教授

    1997年2月 - 2000年12月

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    国名:日本国

  7. 大阪大学   医学部、助教授   助教授

    1991年5月 - 1997年2月

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    国名:日本国

  8. 大阪大学   医学部、助手   助手

    1986年11月 - 1991年5月

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    国名:日本国

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学歴 2

  1. 大阪大学   医学研究科   博士課程

    1984年4月 - 1986年10月

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    国名: 日本国

    備考: 中隊

  2. 大阪大学   医学研究科   医科学修士

    1982年4月 - 1984年3月

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    国名: 日本国

所属学協会 10

  1. 日本神経化学会   理事長

    2013年3月 - 2015年3月

  2. 日本神経化学会   理事

    2017年3月 - 2020年3月

  3. 日本解剖学会   理事/常務理事

    2013年4月 - 2022年3月

  4. 日本神経科学会   理事

    2020年1月 - 現在

  5. 日本自律神経学会   理事

    2009年11月 - 現在

  6. 日本疲労学会   理事

    2017年5月 - 現在

  7. 日本末梢神経学会   評議員

    2000年8月 - 現在

  8. 篤志解剖全国連合会   理事

    2020年3月 - 2022年3月

  9. 国際神経化学会

    1990年 - 現在

  10. 米国神経科学会

    1987年10月 - 現在

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委員歴 6

  1. 第126回日本解剖学会総会学術集会(第98回生理学会との合同大会)   会頭  

    2021年3月   

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    団体区分:学協会

  2. 第22回グリア研究会 大会長   大会長  

    2017年12月   

  3. 第13回日本疲労学会 大会長   大会長  

    2017年5月   

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    団体区分:学協会

  4. 第68回日本自律神経学会 大会長   大会長  

    2015年10月   

  5. 第56回日本神経化学会大会 (Neuro2013合同大会)大会長   大会長  

    2013年6月   

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    団体区分:学協会

  6. 第69回、70回 脳の医学・生物学研究会   代表幹事  

    2020年 - 2022年   

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論文 70

  1. Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction 招待有り 査読有り

    Konishi H*, Okamoto T, Hara Y, Komine O, Tamada H, Maeda M, Osako F, Kobayashi M, Nishiyama A, Kataoka Y, Takai T, Udagawa N, Jung S, Ozato K, Tamura T, Tsuda M, Yamanaka K, Ogi T, Sato K, Kiyama H

    EMBO J     2020年10月

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  2. Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders 招待有り 査読有り

    Nagata Kenichi, Takahashi Mika, Kiryu-Seo Sumiko, Kiyama Hiroshi, Saido Takaomi C.

    ACTA NEUROPATHOLOGICA COMMUNICATIONS   5 巻 ( 1 ) 頁: 83   2017年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Acta neuropathologica communications  

    Endothelin-converting enzyme-like 1 (ECEL1, also termed DINE in rodents), a membrane-bound metalloprotease, has been identified as a gene responsible for distal arthrogryposis (DA). ECEL1-mutated DA is generally characterized by ocular phenotypes in addition to the congenital limb contractures that are common to all DA subtypes. Until now, the consequences of the identified pathogenic mutations have remained incompletely understood because of a lack of detailed phenotypic analyses in relevant mouse models. In this study, we generated a new knock-in mouse strain that carries an ECEL1/DINE pathogenic G607S missense mutation, based on a previous study reporting atypical DA hindlimb phenotypes in two siblings with the mutation. We compared the morphological phenotypes of G607S knock-in mice with C760R knock-in mice that we previously established. Both C760R and G607S knock-in mouse embryos showed similar axonal arborization defects with normal trajectory patterns from the spinal cord to the target hindlimb muscles, as well as axon guidance defects of the abducens nerves. Intriguingly, distinct phenotypes in DINE protein localization and mRNA expression were identified in these knock-in mouse lines. For G607S, DINE mRNA and protein expression was decreased or almost absent in motor neurons. In the C760R mutant mice DINE was expressed and localized in the somata of motor neurons but not in axons. Our mutant mouse data suggest that ECEL1/DINE G607S and C760R mutations both lead to motor innervation defects as primary causes in ECEL1-mutated congenital contracture disorders. However, the functional consequences of the two mutations are distinct, with loss of axonal transport of ECEL1/DINE in C760R mutants and mRNA expression deficits in G607S mutants.

    DOI: 10.1186/s40478-017-0486-9

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  3. Agonists for G-protein-coupled receptor 84 (GPR84) alter cellular morphology and motility but do not induce proinflammatory responses in microglia 招待有り 査読有り

    Wei Li, Tokizane Kyohei, Konishi Hiroyuki, Yu Hua-Rong, Kiyama Hiroshi

    JOURNAL OF NEUROINFLAMMATION   14 巻 ( 1 ) 頁: 198   2017年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Neuroinflammation  

    Background: Several G-protein-coupled receptors (GPCRs) have been shown to be important signaling mediators between neurons and glia. In our previous screening for identification of nerve injury-associated GPCRs, G-protein-coupled receptor 84 (GPR84) mRNA showed the highest up-regulation by microglia after nerve injury. GPR84 is a pro-inflammatory receptor of macrophages in a neuropathic pain mouse model, yet its function in resident microglia in the central nervous system is poorly understood. Methods: We used endogenous, natural, and surrogate agonists for GPR84 (capric acid, embelin, and 6-OAU, respectively) and examined their effect on mouse primary cultured microglia in vitro. Results: 6-n-Octylaminouracil (6-OAU), embelin, and capric acid rapidly induced membrane ruffling and motility in cultured microglia obtained from C57BL/6 mice, although these agonists failed to promote microglial pro-inflammatory cytokine expression. Concomitantly, 6-OAU suppressed forskolin-induced increase of cAMP in cultured microglia. Pertussis toxin, an inhibitor of Gi-coupled signaling, completely suppressed 6-OAU-induced microglial membrane ruffling and motility. In contrast, no 6-OAU-induced microglial membrane ruffling and motility was observed in microglia from DBA/2 mice, a mouse strain that does not express functional GPR84 protein due to endogenous nonsense mutation of the GPR84 gene. Conclusions: GPR84 mediated signaling causes microglial motility and membrane ruffling but does not promote pro-inflammatory responses. As GPR84 is a known receptor for medium-chain fatty acids, those released from damaged brain cells may be involved in the enhancement of microglial motility through GPR84 after neuronal injury.

    DOI: 10.1186/s12974-017-0970-y

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  4. Siglec-H is a microglia-specific marker that discriminates microglia from CNS-associated macrophages and CNS-infiltrating monocytes 招待有り 査読有り

    Konishi Hiroyuki, Kobayashi Masaaki, Kunisawa Taikan, Imai Kenta, Sayo Akira, Malissen Bernard, Crocker Paul R., Sato Katsuaki, Kiyama Hiroshi

    GLIA   65 巻 ( 12 ) 頁: 1927 - 1943   2017年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:GLIA  

    Several types of myeloid cell are resident in the CNS. In the steady state, microglia are present in the CNS parenchyma, whereas macrophages reside in boundary regions of the CNS, such as perivascular spaces, the meninges and choroid plexus. In addition, monocytes infiltrate into the CNS parenchyma from circulation upon blood–brain barrier breakdown after CNS injury and inflammation. Although several markers, such as CD11b and ionized calcium-binding adapter molecule 1 (Iba1), are frequently used as microglial markers, they are also expressed by other types of myeloid cell and microglia-specific markers were not defined until recently. Previous transcriptome analyses of isolated microglia identified a transmembrane lectin, sialic acid-binding immunoglobulin-like lectin H (Siglec-H), as a molecular signature for microglia; however, this was not confirmed by histological studies in the nervous system and the reliability of Siglec-H as a microglial marker remained unclear. Here, we demonstrate that Siglec-H is an authentic marker for microglia in mice by immunohistochemistry using a Siglec-H-specific antibody. Siglec-H was expressed by parenchymal microglia from developmental stages to adulthood, and the expression was maintained in activated microglia under injury or inflammatory condition. However, Siglec-H expression was absent from CNS-associated macrophages and CNS-infiltrating monocytes, except for a minor subset of cells. We also show that the Siglech gene locus is a feasible site for specific targeting of microglia in the nervous system. In conclusion, Siglec-H is a reliable marker for microglia that will allow histological identification of microglia and microglia-specific gene manipulation in the nervous system.

    DOI: 10.1002/glia.23204

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  5. Damage-induced neuronal endopeptidase (DINE) enhances axonal regeneration potential of retinal ganglion cells after optic nerve injury 査読有り

    Kaneko A, Kiryu-Seo S, Matsumoto S, Kiyama H

    Cell Death & Disease   8 巻 ( 6 ) 頁: e2847   2017年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/ccdis.2017.212

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  6. Three-dimensional analysis of somatic mitochondrial dynamics in fission-deficient injured motor neurons using FIB/SEM 査読有り

    Tamada H, Kiryu-Seo S, Hosokawa H, Ohta K, Ishihara N, Nomura M, Mihara K, Nakamura K-I, Kiyama H

    J Comp Neurol   525 巻 ( 11 ) 頁: 2535-2548   2017年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  7. Phospholipid localization implies microglial morphology and function via Cdc42 in vitro 査読有り

    Tokizane K, Konishi H, Makide K, Kawana H, Nakamura S, Kaibuchi K, Ohwada T, Aoki J, Kiyama H

    Glia   65 巻 ( 5 ) 頁: 740-755   2017年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  8. Exposure to diphtheria toxin during the juvenile period impairs both inner and outer hair cells in C57BL/6 mice 査読有り

    Konishi H, Ohgami N, Matsushita A, Kondo Y, Aoyama Y, Kobayashi M, Nagai T, Ugawa S, Yamada K, Kato M, Kiyama H

    Neuroscience   351 巻   頁: 15-23   2017年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  9. ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis 査読有り

    Nagata K, Kiryu-Seo S, Tamada H, Okuyama-Uchimura F, Kiyama H, Saido TC

    Acta Neuropathol   132 巻 ( 1 ) 頁: 111-126   2016年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  10. Motor nerve arborization requires proteolytic domain of Damage-induced neuronal endopeptidase (DINE) during development 査読有り

    Matsumoto S, Kiryu-Seo S, Kiyama H

    J Neurosci   36 巻 ( 17 ) 頁: 4744-4757   2016年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1523/JNEUROSCI.3811-15.2016

  11. TREM2/DAP12 signal elicits pro-inflammatory response in microglia and exacerbates neuropathic pain 査読有り

    Kobayashi M, Konishi H, Sayo A, Takai T, Kiyama H

    J Neurosci   36 巻 ( 43 ) 頁: 11138-11150   2016年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1523/JNEUROSCI.1238-16.2016

  12. Mitochondrial fission is an acute response against injury-induced neurodegeneration 査読有り

    Kiryu-Seo S, Tamada H, Kato Y, Yasuda K, Ishihara N, Nomura M, Mihara K, Kiyama H

    Sci Rep   6 巻   頁: 28331   2016年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/srep28331

  13. Existence of c-Kit negative cells with ultrastructural features of interstitial cells of Cajal in the subserosal layer of the W/Wv mutant mouse colon 査読有り

    Tamada H, Kiyama H

    J Smooth Muscle Res.   51 巻   頁: 1-9   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  14. Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS 査読有り

    Watanabe S, Ilieva H, Tamada H, Nomura H, Komine O, Endo F, Jin S, Mancias P, Kiyama H, Yamanaka K

    EMBO Mol Med   8 巻 ( 12 ) 頁: 1421-1437   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.15252/emmm.201606403

  15. Increased a-series gangliosides positively regulate leptin/Ob receptor-mediated signals in hypothalamus of GD3 synthase-deficient mice 査読有り

    Ji S, Tokizane K, Ohkawa Y, Ohmi Y, BannoR, Okajima T, Kiyama H, Furuawa K, Furukawa K-I

    Biochem Biophys Res Commun   479 巻 ( 3 ) 頁: 453-460   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrc.2016.09.077

  16. Increase of transcription factor EB (TFEB) and lysosomes in rat DRG neurons and their transportation to the central nerve terminal in dorsal horn after nerve injury 査読有り

    Jung J, Uesugi N, Jeong NJ, Park BS, Konishi H, Kiyama H

    Neuroscience   313 巻   頁: 10-22   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.neuroscience.2015.11.028

  17. R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5 査読有り

    Nakashima H, Ohkawara B, Ishigaki S, Fukudome T, Ito K, Tsushima M, Konishi H, Okuno T, Yoshimura T, Ito M, Masuda A, Sobue G, Kiyama H, Ishiguro N, Ohno K

    Sci Rep   6 巻   頁: 28512   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  18. Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy

    Chen G, Masuda A, Konishi H, Ohkawara B, Ito M, Kinoshita M, Kiyama H, Matsuura T, Ohno K

    Sci Rep   2 巻   頁: 25317   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/srep25317

  19. Ontogeny and innervation of taste buds in mouse palatal gustatory epithelium 査読有り

    Rashwan A, Konishi H, El-Sharaby A, Kiyama H

    J Chemical Neuroanat   71 巻   頁: 26-40   2016年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jchemneu.2015.11.003

  20. A DAP12-Dependent Signal Promotes Pro-Inflammatory Polarization in Microglia Following Nerve Injury and Exacerbates Degeneration of Injured Neurons 査読有り

    Kobayashi M, Konishi H, Takai T, Kiyama H

    Glia   63 巻 ( 6 ) 頁: 1073-1082   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  21. Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model 査読有り

    Taguchi T, Katanosaka T, Yasui M, Hayashi K, Yamashita M, Wakatsuki K, Kiyama H, Yamanaka A, Mizumura K

    Pain   156 巻 ( 3 ) 頁: 415-427   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  22. Axonal injury alters the extracellular glial environment of the axon initial segment and allows substantial mitochondrial influx into axon initial segment 招待有り 査読有り

    Tamada Hiromi, Kiryu-Seo Sumiko, Sawada Sohgo, Kiyama Hiroshi

    JOURNAL OF COMPARATIVE NEUROLOGY   529 巻 ( 16 ) 頁: 3621 - 3632   2021年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Comparative Neurology  

    The axon initial segment (AIS) is structurally and functionally distinct from other regions of the axon, yet alterations in the milieu of the AIS after brain injury have not been well characterized. In this study, we have examined extracellular and intracellular changes in the AIS after hypoglossal nerve injury. Microglial adhesions to the AIS were rarely observed in healthy controls, whereas microglial adhesions to the AIS became apparent in the axonal injury model. Regarding intra-AIS morphology, we focused on mitochondria because mitochondrial flow into the injured axon appears critical for axonal regeneration. To visualize mitochondria specifically in injured axons, we used Atf3:BAC transgenic mice whose mitochondria were labeled with GFP in response to nerve injury. These mice clearly showed mitochondrial localization in the AIS after nerve injury. To precisely confirm the light microscopic observations, we performed three-dimensional ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM). Although the healthy AIS was not surrounded by microglia, tight microglial adhesions with thick processes adhering to the AIS were observed after injury. FIB/SEM simultaneously allowed the observation of mitochondrial localization in the AIS. In the AIS of non-injured neurons, few mitochondria were observed, whereas mitochondria were abundantly localized in the cell body, axon hillock, and axon. Intriguingly, in the injured AIS, numerous mitochondria were observed throughout the AIS. Taken together, axonal injury changes the extracellular glial environment surrounding the AIS and intracellular mitochondrial localization in the AIS. These changes would be crucial responses, perhaps for injured neurons to regenerate after axonal injury.

    DOI: 10.1002/cne.25212

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  23. A mouse model of microglia-specific ablation in the embryonic central nervous system. 招待有り 査読有り

    Li C, Konishi H, Nishiwaki K, Sato K, Miyata T, Kiyama H

    Neuroscience research     2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neuroscience Research  

    Microglia, which migrate into the central nervous system (CNS) during the early embryonic stages, are considered to play various roles in CNS development. However, their embryonic roles are largely unknown, partly due to the lack of an effective microglial ablation system in the embryo. Here, we show a microglial ablation model by injecting diphtheria toxin (DT) into the amniotic fluid of Siglechdtr mice, in which the gene encoding DT receptor is knocked into the microglia-specific gene locus Siglech. We revealed that embryonic microglia were depleted for several days throughout the CNS, including some regions where microglia transiently accumulated, at any embryonic time point from embryonic day 10.5, when microglia colonize the CNS. This ablation system was specific for microglia because CNS-associated macrophages, which are a distinct population from microglia that reside in the CNS interfaces such as meninges, were unaffected. Therefore, this microglial ablation system is highly effective for studying the embryonic functions of microglia.

    DOI: 10.1016/j.neures.2021.06.002

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  24. TC10, a Rho family GTPase, is required for efficient axon regeneration in a neuron-autonomous manner 招待有り 査読有り

    Koinuma Shingo, Negishi Ryota, Nomura Riko, Sato Kazuki, Kojima Takuya, Segi-Nishida Eri, Goitsuka Ryo, Iwakura Yoichiro, Wada Naoyuki, Koriyama Yoshiki, Kiryu-Seo Sumiko, Kiyama Hiroshi, Nakamura Takeshi

    JOURNAL OF NEUROCHEMISTRY   157 巻 ( 4 ) 頁: 1196 - 1206   2021年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Neurochemistry  

    Intracellular signaling pathways that promote axon regeneration are closely linked to the mechanism of neurite outgrowth. TC10, a signaling molecule that acts on neurite outgrowth through membrane transport, is a member of the Rho family G proteins. Axon injury increases the TC10 levels in motor neurons, suggesting that TC10 may be involved in axon regeneration. In this study, we tried to understand the roles of TC10 in the nervous system using TC10 knock-out mice. In cultured hippocampal neurons, TC10 ablation significantly reduced axon elongation without affecting ordinary polarization. We determined a role of TC10 in microtubule stabilization at the growth cone neck; therefore, we assume that TC10 limits axon retraction and promotes in vitro axon outgrowth. In addition, there were no notable differences in the size and structure of brains during prenatal and postnatal development between wild-type and TC10 knock-out mice. In motor neurons, axon regeneration after injury was strongly suppressed in mice lacking TC10 (both in conventional and injured nerve specific deletion). In retinal ganglion cells, TC10 ablation suppressed the axon regeneration stimulated by intraocular inflammation and cAMP after optic nerve crush. These results show that TC10 plays an important role in axon regeneration in both the peripheral and central nervous systems, and the role of TC10 in peripheral axon regeneration is neuron-intrinsic. (Figure presented.).

    DOI: 10.1111/jnc.15235

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  25. Morphology, localization, and postnatal development of dural macrophages 招待有り 査読有り

    Sato Takehito, Konishi Hiroyuki, Tamada Hiromi, Nishiwaki Kimitoshi, Kiyama Hiroshi

    CELL AND TISSUE RESEARCH   384 巻 ( 1 ) 頁: 49 - 58   2021年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cell and Tissue Research  

    The dura mater contains abundant macrophages whose functions remain largely elusive. Recent studies have demonstrated the origin, as well as the gene expression pattern, of dural macrophages (dMΦs). However, their histological features have not been explored yet. In this study, we performed immunohistochemistry and electron microscopy to elucidate their precise morphology, localization, and postnatal development in mice. We found that the morphology, as well as the localization, of dMΦs changed during postnatal development. In neonatal mice, dMΦ exhibited an amoeboid morphology. During postnatal development, their cell bodies elongated longitudinally and became aligned along dural blood vessels. In adulthood, nearly half of the dMΦs aligned along blood vessel networks. However, most of these cells were not directly attached to vessels; pericytes and fibroblasts interposed between dMΦs and vessels. This morphological information may provide further indications for the functional significance of dMΦs.

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  26. Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model 招待有り 査読有り

    Koshimizu Hiroyuki, Ohkawara Bisei, Nakashima Hiroaki, Ota Kyotaro, Kanbara Shunsuke, Inoue Taro, Tomita Hiroyuki, Sayo Akira, Kiryu-Seo Sumiko, Konishi Hiroyuki, Ito Mikako, Masuda Akio, Ishiguro Naoki, Imagama Shiro, Kiyama Hiroshi, Ohno Kinji

    LIFE SCIENCES   263 巻   頁: 118577   2020年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Life Sciences  

    Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation.

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  27. Non-pathological roles of microglial TREM2/DAP12: TREM2/DAP12 regulates the physiological functions of microglia from development to aging 招待有り 査読有り

    Konishi Hiroyuki, Kiyama Hiroshi

    NEUROCHEMISTRY INTERNATIONAL   141 巻   頁: 104878   2020年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neurochemistry International  

    Triggering receptor expressed on myeloid cells 2 (TREM2) forms a receptor complex with DNAX-activating protein of 12 kDa (DAP12) on the microglial plasma membrane. A wide variety of protein and non-protein ligands, including lipids and DNA, can bind to TREM2, inducing the activation of microglia via DAP12. Both Trem2 and Dap12 have been identified as causative genes for Nasu-Hakola disease, which causes presenile dementia in association with bone cysts. Furthermore, TREM2/DAP12 signaling represents an essential inducer of the activated microglial phenotype in neuronal diseases, including Alzheimer's disease. Therefore, most previous studies examining TREM2/DAP12 have focused on their roles in microglia under pathological conditions. However, a growing body of evidence has demonstrated the involvement of TREM2/DAP12 signaling in the regulation of physiological functions in microglia. Accordingly, by examining the importance of TREM2/DAP12 in the regulation of microglial activity during development, homeostasis, and aging in the brain, this review elucidates the roles played by this complex in the healthy brain.

    DOI: 10.1016/j.neuint.2020.104878

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  28. Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction 招待有り 査読有り

    Konishi Hiroyuki, Okamoto Takayuki, Hara Yuichiro, Komine Okiru, Tamada Hiromi, Maeda Mitsuyo, Osako Fumika, Kobayashi Masaaki, Nishiyama Akira, Kataoka Yosky, Takai Toshiyuki, Udagawa Nobuyuki, Jung Steffen, Ozato Keiko, Tamura Tomohiko, Tsuda Makoto, Yamanaka Koji, Ogi Tomoo, Sato Katsuaki, Kiyama Hiroshi

    EMBO JOURNAL   39 巻 ( 22 ) 頁: e104464   2020年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EMBO Journal  

    Microglia are the principal phagocytes that clear cell debris in the central nervous system (CNS). This raises the question, which cells remove cell debris when microglial phagocytic activity is impaired. We addressed this question using Siglechdtr mice, which enable highly specific ablation of microglia. Non-microglial mononuclear phagocytes, such as CNS-associated macrophages and circulating inflammatory monocytes, did not clear microglial debris. Instead, astrocytes were activated, exhibited a pro-inflammatory gene expression profile, and extended their processes to engulf microglial debris. This astrocytic phagocytosis was also observed in Irf8-deficient mice, in which microglia were present but dysfunctional. RNA-seq demonstrated that even in a healthy CNS, astrocytes express TAM phagocytic receptors, which were the main astrocytic phagocytic receptors for cell debris in the above experiments, indicating that astrocytes stand by in case of microglial impairment. This compensatory mechanism may be important for the maintenance or prolongation of a healthy CNS.

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  29. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation 招待有り 査読有り

    Haruwaka Koichiro, Ikegami Ako, Tachibana Yoshihisa, Ohno Nobuhiko, Konishi Hiroyuki, Hashimoto Akari, Matsumoto Mami, Kato Daisuke, Ono Riho, Kiyama Hiroshi, Moorhouse Andrew J., Nabekura Junichi, Wake Hiroaki

    NATURE COMMUNICATIONS   10 巻 ( 1 ) 頁: 5816   2019年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Communications  

    Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood–brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.

    DOI: 10.1038/s41467-019-13812-z

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  30. The Link between Type III Reg and STAT3-Associated Cytokines in Inflamed Colonic Tissues 招待有り 査読有り

    Xu Xin, Fukui Hirokazu, Ran Ying, Wang Xuan, Inoue Yoshihito, Ebisudani Nobuhiko, Nishimura Heihachiro, Tomita Toshihiko, Oshima Tadayuki, Watari Jiro, Kiyama Hiroshi, Miwa Hiroto

    MEDIATORS OF INFLAMMATION   2019 巻   頁: 7859460   2019年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Mediators of Inflammation  

    Reg (regenerating gene) family proteins are known to be overexpressed in gastrointestinal (GI) tissues under conditions of inflammation. However, the pathophysiological significance of Reg family protein overexpression and its regulation is still unclear. In the present study, we investigated the profile of Reg family gene expression in a colitis model and focused on the regulation of Reg IIIβ and IIIγ, which are overexpressed in inflamed colonic mucosa. C57BL/6 mice were administered 2% dextran sulfate sodium (DSS) in drinking water for five days, and their colonic tissues were investigated histopathologically at interval for up to 12 weeks. Gene expression of the Reg family and cytokines (IL-6, IL-17, and IL-22) was evaluated by real-time RT-PCR, and Reg IIIβ/γ expression was examined by immunohistochemistry. The effects of cytokines on STAT3 phosphorylation and HIP/PAP (type III REG) expression in Caco2 and HCT116 cells were examined by Western blot analysis. Among Reg family genes, Reg IIIβ and IIIγ were alternatively overexpressed in the colonic tissues of mice with DSS-induced colitis. The expression of STAT3-associated cytokines (IL-6, IL-17, and IL-22) was also significantly increased in those tissues, being significantly correlated with that of Reg IIIβ/γ. STAT3 phosphorylation and HIP/PAP expression were significantly enhanced in Caco2 cells upon stimulation with IL-6, IL-17, and IL-22. In HCT116 cells, those enhancements were also observed by IL-6 and IL-22 stimulations but not IL-17. The link between type III Reg and STAT3-associated cytokines appears to play a pivotal role in the pathophysiology of DSS-induced colitis.

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  31. Dual Microglia Effects on Blood Brain Barrier Permeability Induced by Systemic Inflammation 招待有り 査読有り

    Haruwaka K, Ikegami A, Tachibana Y, Ohno N, Konishi H, Hashimoto A, Matsumoto M, Kato D, Ono R, Kiyama H, Moorhouse A, Nabekura J, and Wake H

    Nat Commun     2019年11月

  32. Dual functions of microglia in the formation and refinement of neural circuits during development 招待有り 査読有り

    Konishi Hiroyuki, Kiyama Hiroshi, Ueno Masaki

    INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE   77 巻   頁: 18 - 25   2019年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Developmental Neuroscience  

    Microglia colonize the central nervous system (CNS) parenchyma during embryogenesis and contribute to various developmental processes leading to the formation of refined neural circuits. In this review, we focus on the bidirectional function of microglia during normal CNS development and discuss recent perspectives on the functions of microglia in neural circuit formation. Microglia participate in neurogenesis, migration, axonal growth, and synapse formation and remodeling, all of which are fundamental for the establishment of neural networks, by secreting a variety of molecules toward neurons and phagocytosing both live and dying neurons or their debris. Intriguingly, microglia play dual roles in each of the neurodevelopmental processes that they affect. For instance, microglia modulate synapse numbers by both promoting the formation of new synapses and eliminating unnecessary synapses. The study of the developmental roles of microglia is essential not only for understanding normal CNS development but also for preventing developmental brain disorders caused by microglial dysfunction.

    DOI: 10.1016/j.ijdevneu.2018.09.009

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  33. Astrocytic phagocytosis as a compensated function of microglial dysfunction 招待有り 査読有り

    Konishi H., Kiyama H.

    GLIA   67 巻   頁: E534 - E534   2019年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  34. New Insights of a Neuronal Peptidase DINE/ECEL1: Nerve Development, Nerve Regeneration and Neurogenic Pathogenesis 招待有り 査読有り

    Kiryu-Seo Sumiko, Nagata Kenichi, Saido Takaomi C., Kiyama Hiroshi

    NEUROCHEMICAL RESEARCH   44 巻 ( 6 ) 頁: 1279 - 1288   2019年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neurochemical Research  

    Our understanding of the physiological relevance of unique Damage-induced neuronal endopeptidase (DINE) [also termed Endothelin-converting enzyme-like 1 (ECEL1)] has recently expanded. DINE/ECEL1 is a type II membrane-bound metalloprotease, belonging to a family including the neprilysin (NEP) and endothelin-converting enzyme (ECE). The family members degrade and/or process peptides such as amyloid β and big-endothelins, which are closely associated with pathological conditions. Similar to NEP and ECE, DINE has been expected to play an important role in injured neurons as well as in developing neurons, because of its remarkable transcriptional response to neuronal insults and predominant neuronal expression from the embryonic stage. However, the physiological significance of DINE has long remained elusive. In the last decade, a series of genetically manipulated mice have driven research progress to elucidate the physiological aspects of DINE. The mice ablating Dine fail to arborize the embryonic motor axons in some subsets of muscles, including the respiratory muscles, and die immediately after birth. The abnormal phenotype of motor axons is also caused by one amino acid exchanges of DINE/ECEL1, which are responsible for distal arthrogryposis type 5 in a group of human congenital movement disorders. Furthermore, the mature Dine-deficient mice in which the lethality is rescued by genetic manipulation have shown the involvement of DINE in central nervous system regeneration. Here we describe recent research advances that DINE-mediated proteolytic processes are critical for nerve development, regeneration and pathogenesis, and discuss the future potential for DINE as a therapeutic target for axonal degeneration/disorder.

    DOI: 10.1007/s11064-018-2665-x

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  35. Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis 招待有り 査読有り

    Shindo Ryodai, Ohmuraya Masaki, Komazawa-Sakon Sachiko, Miyake Sanae, Deguchi Yutaka, Yamazaki Soh, Nishina Takashi, Yoshimoto Takayuki, Kakuta Soichiro, Koike Masato, Uchiyama Yasuo, Konishi Hiroyuki, Kiyama Hiroshi, Mikami Tetuo, Moriwaki Kenta, Araki Kimi, Nakano Hiroyasu

    ISCIENCE   15 巻   頁: 536 - +   2019年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:iScience  

    Immunology; Immune Response; Cell Biology; Functional Aspects of Cell Biology

    DOI: 10.1016/j.isci.2019.05.011

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  36. GPR34 in spinal microglia exacerbates neuropathic pain in mice 招待有り 査読有り

    Sayo Akira, Konishi Hiroyuki, Kobayashi Masaaki, Kano Kuniyuki, Kobayashi Hiroki, Hibi Hideharu, Aoki Junken, Kiyama Hiroshi

    JOURNAL OF NEUROINFLAMMATION   16 巻 ( 1 ) 頁: 82   2019年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Neuroinflammation  

    Background: Neuropathic pain is caused by sensory nerve injury, but effective treatments are currently lacking. Microglia are activated in the spinal dorsal horn after sensory nerve injury and contribute to neuropathic pain. Accordingly, molecules expressed by these cells are considered potential targets for therapeutic strategies. Our previous gene screening study using a mouse model of motor nerve injury showed that the G-protein-coupled receptor 34 gene (GPR34) is induced by nerve injury. Because GPR34 is now considered a microglia-enriched gene, we explored the possibility that it might be involved in microglial activation in the dorsal horn in a mouse model of neuropathic pain. Methods: mRNA expression of GPR34 and pro-inflammatory molecules was determined by quantitative real-time PCR in wild-type and GPR34-deficient mice with L4 spinal nerve injury. In situ hybridization was used to identify GPR34 expression in microglia, and immunohistochemistry with the microglial marker Iba1 was performed to examine microglial numbers and morphology. Mechanical sensitivity was evaluated by the von Frey hair test. Liquid chromatography-tandem mass spectrometry quantified expression of the ligand for GPR34, lysophosphatidylserine (LysoPS), in the dorsal horn, and a GPR34 antagonist was intrathecally administrated to examine the effect of inhibiting LysoPS-GPR34 signaling on mechanical sensitivity. Results: GPR34 was predominantly expressed by microglia in the dorsal horn after L4 nerve injury. There were no histological differences in microglial numbers or morphology between WT and GPR34-deficient mice. However, nerve injury-induced pro-inflammatory cytokine expression levels in microglia and pain behaviors were significantly attenuated in GPR34-deficient mice. Furthermore, the intrathecal administration of the GPR34 antagonist reduced neuropathic pain. Conclusions: Inhibition of GPR34-mediated signal by GPR34 gene deletion reduced nerve injury-induced neuropathic pain by suppressing pro-inflammatory responses of microglia without affecting their morphology. Therefore, the suppression of GPR34 activity may have therapeutic potential for alleviating neuropathic pain.

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  37. Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome 招待有り 査読有り

    Yasui Masaya, Menjyo Yuki, Tokizane Kyohei, Shiozawa Akiko, Tsuda Makoto, Inoue Kazuhide, Kiyama Hiroshi

    JOURNAL OF NEUROINFLAMMATION   16 巻 ( 1 ) 頁: 67   2019年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Neuroinflammation  

    Background: Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model. Methods: Chronic or continuous stress-loading (CS) model rats, housed in a cage with a thin level of water (1.5 cm in depth), were used. The von Frey test and pressure pain test were employed to measure pain behavior. The neuronal and microglial activations were immunohistochemically demonstrated with antibodies against ATF3 and Iba1. Electromyography was used to evaluate muscle activity. Results: The expression of ATF3, a marker of neuronal hyperactivity or injury, was first observed in the lumbar dorsal root ganglion (DRG) neurons 2 days after CS initiation. More than 50% of ATF3-positive neurons simultaneously expressed the proprioceptor markers TrkC or VGluT1, whereas the co-expression rates for TrkA, TrkB, IB4, and CGRP were lower than 20%. Retrograde labeling using fluorogold showed that ATF3-positive proprioceptive DRG neurons mainly projected to the soleus. Substantial microglial accumulation was observed in the medial part of the dorsal horn on the fifth CS day. Microglial accumulation was observed around a subset of motor neurons in the dorsal part of the ventral horn on the sixth CS day. The motor neurons surrounded by microglia were ATF3-positive and mainly projected to the soleus. Electromyographic activity in the soleus was two to three times higher in the CS group than in the control group. These results suggest that chronic proprioceptor activation induces the sequential activation of neurons along the spinal reflex arc, and the neuronal activation further activates microglia along the arc. Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior. Conclusion: Our results indicate that proprioceptor-induced microglial activation may be a key player in the initiation and maintenance of abnormal pain in patients with CFS.

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  38. Mitochondrial behavior during axon regeneration/degeneration in vivo 招待有り 査読有り

    Kiryu-Seo Sumiko, Kiyama Hiroshi

    NEUROSCIENCE RESEARCH   139 巻   頁: 42 - 47   2019年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neuroscience Research  

    Over the last decade, mitochondrial dynamics beyond function during axon regeneration/degeneration have received attention. Axons have an effective delivery system of mitochondria shuttling between soma and axonal terminals, due to their polarized structure. The proper axonal transport of mitochondria, coordinated with mitochondrial fission/fusion and clearance, is vital for supplying high power energy in injured axons. Many researchers have studied mitochondrial dynamics using in vitro cultured cells with significant progress reported. However, the in vitro culture system is missing a physiological environment including glial cells, immune cells, and endothelial cells, whose communications are indispensable to nerve regeneration/degeneration. In line with this, the understanding of mitochondrial behavior in injured axon in vivo is necessary for promoting the physiological understanding of damaged axons and the development of a therapeutic strategy. In this review, we focus on recent insights into in vivo mitochondrial dynamics during axonal regeneration/degeneration, and introduce the advances of mouse strains to visualize mitochondria in a neuron-specific or an injury-specific manner, which are extremely useful for nerve regeneration/degeneration studies.

    DOI: 10.1016/j.neures.2018.08.014

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  39. Branched Sialylated N-glycans Are Accumulated in Brain Synaptosomes and Interact with Siglec-H. 招待有り 査読有り

    Handa-Narumi M, Yoshimura T, Konishi H, Fukata Y, Manabe Y, Tanaka K, Bao GM, Kiyama H, Fukase K, Ikenaka K

    Cell structure and function   43 巻 ( 2 ) 頁: 141 - 152   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cell Structure and Function  

    Proper N-glycosylation of proteins is important for normal brain development and nervous system function. Identification of the localization, carrier proteins and interacting partners of N-glycans is essential for understanding the roles of glycoproteins. The present study examined the N-glycan A2G'2F (Galβ1-3GlcNAcβ1-2Manα1-6[Galβ1-3GlcNAcβ1-2Manα1-3]Manβ1-4GlcNAcβ1-4[Fucα1-6]GlcNAc-). A2G'2F has a branched sialic acid structural feature, and branched sialylated A2G'2F is a major N-glycan in the mouse brain. Its expression in the mouse brain increases during development, suggesting that branched sialylated Nglycans play essential roles during brain development. However, the carrier proteins, interacting partners and localization of branched sialylated N-glycans remain unknown. We previously improved our method for analyzing N-glycans from trace samples, and here we succeeded in detecting A2G'2F in small fragments excised from the two-dimensional electrophoresis gels of subcellular fractionated mouse brain proteins. A2G'2F was accumulated in mouse brain synaptosomes. We identified calreticulin as one of the candidate A2G'2F carriers and found calreticulin expression in both the endoplasmic reticulum and synaptosomal fractions. Calreticulin was observed in dendritic spines of cultured cortical neurons. Synthesized branched sialylated glycan clusters interacted with sialic acid-binding immunoglobulin-like lectin H (Siglec-H), which is known to be a microgliaspecific molecule. Taken together, these results suggest that branched sialylated A2G'2F in synaptosomes plays a role in the interaction of dendritic spines with microglia.

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  40. Microglial TREM2/DAP12 Signaling: A Double-Edged Sword in Neural Diseases 招待有り 査読有り

    Konishi Hiroyuki, Kiyama Hiroshi

    FRONTIERS IN CELLULAR NEUROSCIENCE   12 巻   頁: 206   2018年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers in Cellular Neuroscience  

    Microglia are activated after neuronal injury and in neurodegenerative diseases, and trigger neuroinflammation in the central nervous system (CNS). Microglia-derived neuroinflammation has both beneficial and detrimental effects on neurons. Because the timing and magnitude of microglial activation is thought to be a critical determinant of neuronal fate, understanding the molecular mechanisms underlying microglial activation is required to enable establishment of microglia-targeted therapies for neural diseases. Plasma membrane receptors play primary roles as activators of microglia and in this review, we focus on a receptor complex involving triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), both of which are causative genes for Nasu-Hakola disease, a dementia with bone cysts. Recent transcriptome approaches demonstrated TREM2/DAP12 signaling as the principal regulator that transforms microglia from a homeostatic to a neural disease-associated state. Furthermore, animal model studies revealed critical roles for TREM2/DAP12 in the regulation of microglial activity, including survival, phagocytosis, and cytokine production, not only in Alzheimer's disease but also in other neural diseases, such as Parkinson's disease, demyelinating disease, ischemia, and peripheral nerve injury. Intriguingly, while TREM2/DAP12-mediated microglial activation is detrimental for some diseases, including peripheral nerve injury, it is beneficial for other diseases. As the role of activated microglia differs among disease models, TREM2/DAP12 signaling may result in different outcomes in different diseases. In this review we discuss recent perspectives on the role of TREM2/DAP12 in microglia and their contribution to neural diseases.

    DOI: 10.3389/fncel.2018.00206

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  41. Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion 招待有り 査読有り

    Nakano Tomonori, Kurimoto Shigeru, Kato Shuichi, Asano Kenichi, Hirata Takuma, Kiyama Hiroshi, Hirata Hitoshi

    JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE   12 巻 ( 6 ) 頁: 1469 - 1480   2018年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Tissue Engineering and Regenerative Medicine  

    Neurogenesis in the adult peripheral nervous system remains to be demonstrated. We transplanted embryonic neural stem cells into a Wallerian degenerating nerve graft and observed development of a nodular structure consisting of neurons, glia, and Schwann cells. Histological analysis revealed a structure loosely resembling the spinal cord, including a synaptic network that formed along the neuron. Furthermore, the new axons reinnervated the paralysed muscle, forming both de novo and revived neuromuscular junctions. Reinnervation of the paralysed muscle resulted in significantly greater mean wet muscle weight and muscle fibre cross-sectional area on the cell transplantation side than on the surgical control side (body weight 0.071 ± 0.011% vs. 0.051 ± 0.007%, p =.006; area 355.6 ± 345.2 vs. 114.0 ± 132.0 μm2, p <.001). Electrophysiological experiments demonstrated a functional connection between the neurons and muscle; hence, we identified this nodule as an ectopic ganglion. Surprisingly, in green rat experiments, most of these glial cells, but none of the neurons, expressed enhanced green fluorescent protein, suggesting that the cells constituting the ectopic ganglion were derived from both transplanted stem cells and endogenous stem cells. Such adult neurogenesis in a peripheral nerve related to neural stem cell transplantation has not been reported previously, and these results form the basis for a novel regenerative medicine approach in paralysed muscle.

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  42. Lack of Fgf18 causes abnormal clustering of motor nerve terminals at the neuromuscular junction with reduced acetylcholine receptor clusters 招待有り 査読有り

    Ito Kenyu, Ohkawara Bisei, Yagi Hideki, Nakashima Hiroaki, Tsushima Mikito, Ota Kyotaro, Konishi Hiroyuki, Masuda Akio, Imagama Shiro, Kiyama Hiroshi, Ishiguro Naoki, Ohno Kinji

    SCIENTIFIC REPORTS   8 巻 ( 1 ) 頁: 434   2018年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    FGF receptor 2 is involved in the formation of the neuromuscular junction (NMJ), but its in vivo ligand remains to be determined. Laser capture microdissection of the mouse spinal motor neurons (SMNs) revealed that Fgf18 mRNA is highly expressed in SMNs in adults. Expression of Fgf18 mRNA was the highest in the spinal cord at embryonic day (E) 15.5, which gradually decreased to postnatal day 7. FGF18 protein was localized at the NMJs of the tibialis anterior muscle at E18.5 and in adults. Fgf18-/- mice at E18.5 showed decreased expressions of the NMJ-specific Chrne and Colq genes in the diaphragm. In Fgf18-/- diaphragms, the synaptophysin-positive areas at the nerve terminals and the acetylcholine receptor (AChR)-positive areas at the motor endplates were both approximately one-third of those in wild-type embryos. Fgf18-/- diaphragms ultrastructurally showed abnormal aggregation of multiple nerve terminals making a gigantic presynapse with sparse synaptic vesicles, and simplified motor endplates. In Fgf18-/- diaphragms, miniature endplate potentials were low in amplitude with markedly reduced frequency. In C2C12 myotubes, FGF18 enhanced AChR clustering, which was blocked by inhibiting FGFRs or MEK1. We propose that FGF18 plays a pivotal role in AChR clustering and NMJ formation in mouse embryogenesis.

    DOI: 10.1038/s41598-017-18753-5

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  43. Collapse of mitochondria-associated membrane as common pathomechanism for amyotrophic lateral sclerosis

    Watanabe S., Ilieva H., Tamada H., Nomura H., Komine O., Endo F., Jin S., Mancias P., Kiyama H., Yamanaka K.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   381 巻   頁: 104-104   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jns.2017.08.334

    Web of Science

  44. Three-dimensional analysis of somatic mitochondrial dynamics in fission-deficient injured motor neurons using FIB/SEM 招待有り 査読有り

    Tamada Hiromi, Kiryu-Seo Sumiko, Hosokawa Hiroki, Ohta Keisuke, Ishihara Naotada, Nomura Masatoshi, Mihara Katsuyoshi, Nakamura Kei-ichiro, Kiyama Hiroshi

    JOURNAL OF COMPARATIVE NEUROLOGY   525 巻 ( 11 ) 頁: 2535 - 2548   2017年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Comparative Neurology  

    Mitochondria undergo morphological changes through fusion and fission for their quality control, which are vital for neuronal function. In this study, we examined three-dimensional morphologies of mitochondria in motor neurons under normal, nerve injured, and nerve injured plus fission-impaired conditions using the focused ion beam/scanning electron microscopy (FIB/SEM), because the FIB/SEM technology is a powerful tool to demonstrate both 3D images of whole organelle and the intra-organellar structure simultaneously. Crossing of dynamin-related protein 1 (Drp1) gene-floxed mice with neuronal injury-specific Cre driver mice, Atf3:BAC Tg mice, allowed for Drp1 ablation specifically in injured neurons. FIB/SEM analysis demonstrated that somatic mitochondrial morphologies in motor neurons were not altered before or after nerve injury. However, the fission impairment resulted in prominent somatic mitochondrial enlargement, which initially induced complex morphologies with round regions and long tubular processes, subsequently causing a decrease in the number of processes and further enlargement of the round regions, which eventually resulted in big spheroidal mitochondria without processes. The abnormal mitochondria exhibited several degradative morphologies: local or total cristae collapse, vacuolization, and mitophagy. These suggest that mitochondrial fission is crucial for maintaining mitochondrial integrity in injured motor neurons, and multiple forms of mitochondria degradation may accelerate neuronal degradation.

    DOI: 10.1002/cne.24213

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  45. Damage-induced neuronal endopeptidase (DINE) enhances axonal regeneration potential of retinal ganglion cells after optic nerve injury 招待有り 査読有り

    Kaneko Aoi, Kiryu-Seo Sumiko, Matsumoto Sakiko, Kiyama Hiroshi

    CELL DEATH & DISEASE   8 巻 ( 6 ) 頁: e2847   2017年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cell death &amp; disease  

    Damage-induced neuronal endopeptidase (DINE)/endothelin-converting enzyme-like 1 (ECEL1) is a membrane-bound metalloprotease that we identified as a nerve regeneration-associated molecule. The expression of DINE is upregulated in response to nerve injury in both the peripheral and central nervous systems, while its transcription is regulated by the activating transcription factor 3 (ATF3), a potent hub-transcription factor for nerve regeneration. Despite its unique hallmark of injury-induced upregulation, the physiological relevance of DINE in injured neurons has been unclear. In this study, we have demonstrated that the expression of DINE is upregulated in injured retinal ganglion cells (RGCs) in a coordinated manner with that of ATF3 after optic nerve injury, whereas DINE and ATF3 are not observed in any normal retinal cells. Recently, we have generated a mature DINE-deficient (KOTg) mouse, in which exogenous DINE is overexpressed specifically in embryonic motor neurons to avoid aberrant arborization of motor nerves and lethality after birth that occurs in the conventional DINE KO mouse. The DINE KOTg mice did not show any difference in retinal structure and the projection to brain from that of wild-type (wild type) mice under normal conditions. However, injured RGCs of DINE KOTg mice failed to regenerate even after the zymosan treatment, which is a well-known regeneration-promoting reagent. Furthermore, a DINE KOTg mouse crossed with a Atf3:BAC Tg mouse, in which green fluorescent protein (GFP) is visualized specifically in injured RGCs and optic nerves, has verified that DINE deficiency leads to regeneration failure. These findings suggest that injury-induced DINE is a crucial endopeptidase for injured RGCs to promote axonal regeneration after optic nerve injury. Thus, a DINE-mediated proteolytic mechanism would provide us with a new therapeutic strategy for nerve regeneration.

    DOI: 10.1038/cddis.2017.212

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  46. Phospholipid re-localization induces microglial ramification 招待有り 査読有り

    Tokizane K., Konishi H., Makide K., Kawana H., Nakamuta S., Kaibuchi K., Ohwada T., Aoki J., Kiyama H.

    GLIA   65 巻   頁: E156 - E157   2017年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Web of Science

  47. EXPOSURE TO DIPHTHERIA TOXIN IMPAIRS BOTH INNER AND OUTER DURING THE JUVENILE PERIOD HAIR CELLS IN C57BL/6 MICE 招待有り 査読有り

    Konishi Hiroyuki, Ohgami Nobutaka, Matsushita Aika, Kondo Yuki, Aoyama Yuki, Kobayashi Masaaki, Nagai Taku, Ugawa Shinya, Yamada Akiyofumi, Kato Masashi, Kiyama Hiroshi

    NEUROSCIENCE   351 巻   頁: 15 - 23   2017年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neuroscience  

    Diphtheria toxin (DT) administration into transgenic mice that express the DT receptor (DTR) under control of specific promoters is often used for cell ablation studies in vivo. Because DTR is not expressed in mice, DT injection has been assumed to be nontoxic to cells in vivo. In this study, we demonstrated that DT application during the juvenile stage leads to hearing loss in wild-type mice. Auditory brainstem response measurement showed severe hearing loss in C57BL/6 mice administered DT during the juvenile period, and the hearing loss persisted into adulthood. However, ototoxicity did not occur when DT was applied on postnatal day 28 or later. Histological studies demonstrated that hearing loss was accompanied by significant degeneration of inner and outer hair cells (HCs), as well as spiral ganglion neurons. Scanning electron microscopy showed quick degeneration of inner HCs within 3 days and gradual degeneration of outer HCs within 1 week. These results demonstrated that DT has ototoxic action on C57BL/6 mice during the juvenile period, but not thereafter, and the hearing loss was due to degeneration of inner and outer HCs by unknown DT-related mechanisms.

    DOI: 10.1016/j.neuroscience.2017.03.028

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  48. Phospholipid localization implies microglial morphology and function via Cdc42 in vitro 招待有り 査読有り

    Tokizane Kyohei, Konishi Hiroyuki, Makide Kumiko, Kawana Hiroki, Nakamuta Shinichi, Kaibuchi Kozo, Ohwada Tomohiko, Aoki Junken, Kiyama Hiroshi

    GLIA   65 巻 ( 5 ) 頁: 740 - 755   2017年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:GLIA  

    Under a quiescent state, microglia exhibit a ramified shape, rather than the amoeboid-like morphology following injury or inflammation. The manipulation of microglial morphology in vitro has not been very successful, which has impeded the progress of microglial studies. We demonstrate that lysophosphatidylserine (LysoPS), a kind of lysophospholipids, rapidly and substantially alters the morphology of primary cultured microglia to an in vivo-like ramified shape in a receptor independent manner. This mechanism is mediated by Cdc42 activity. LysoPS is incorporated into the plasma membrane and converted to phosphatidylserine (PS) via the Lands' cycle. The accumulated PS on the membrane recruits Cdc42. Both Cdc42 and PS colocalize predominantly in primary and secondary processes, but not in peripheral branches or tips of microglia. Along with the morphological changes LysoPS suppresses inflammatory cytokine production and NF-kB activity. The present study provides a tool to manipulate a microglial phenotype from an amoeboid to a fully ramified in vitro, which certainly contributes to studies exploring microglial physiology and pathology.

    DOI: 10.1002/glia.23123

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  49. Beta-series gangliosides crucially regulate leptin secretion in adipose tissues

    Shuting Ji, Ohkawa Y, Tokizane K, Ohmi Y, Banno R, FurukawaK, Kiyama H, Furukawa K

    Biochem Biophys Res Commun   459 巻 ( 2 ) 頁: 189-195   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  50. Effects of Nutritional Supplementation on Fatigue, and Autonomic and Immune Dysfunction in Patients with End-Stage Renal Disease: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial 査読有り

    Fukuda S, Koyama H, Kondo K, Fujii H, Hirayama Y, Tabata T, Okamura M, Yamakawa T, Okada S, Hirata S, Kiyama H, Kajimoto O, Watanabe Y, Inaba M, Nishizawa Y

    PLoS One   10 巻 ( 3 ) 頁: e0119578   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  51. Interferon regulatory factor 8 expressed in microglia contributes to tactile allodynia induced by repeated cold stress in rodents 査読有り

    Akagi T, Matsumura Y, Yasui M, Minami E, Inoue H, Masuda T, Tozaki-Saitoh H, Tamura T, Mizumura K, Tsuda M, Kiyama H, Inoue K

      126 巻 ( 2 ) 頁: 172-176   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  52. Down-regulation of KCC2 expression and phosphorylation in motoneurons, and increases the number of in primary afferent projections to motoneurons in mice with post-stroke spasticity 査読有り

    Toda T, Ishida K, Kiyama H, Yamashita T, Lee S

    PLoS One   9 巻 ( 12 ) 頁: e114328   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  53. A chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation

    Yasui M, Yoshimura T, Takeuchi S, Tokizane K, Tsuda M, Inoue K, Kiyama H

    Glia   62 巻 ( 9 ) 頁: 1407-1417   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  54. Weakened rate-dependent depression of Hoffmann's reflex and increased motoneuron hyperactivity after motor cortical infarction in mice

    Lee S, TodaT, Kiyama H, and Yamashita T

    Cell Death & Disease   5 巻   頁: e1007   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  55. microRNA-124 is down regulated in nerve injured motor neurons and it potentially targets mRNAs for KLF6 and STAT3 査読有り

    Nagata K, Hama I, Kiryu-Seo S and Kiyama H

    Neuroscience   256 巻   頁: 426-432   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  56. Continuous stress promotes expression of VGF in melanotroph via suppression of dopamine 査読有り

    Tokizane K, Konishi H, Yasui M, Ogawa T, Sasaki K, Minamino N, Kiyama H

    Mol Cell Endocrinol   372 巻 ( 1-2 ) 頁: 49-56   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  57. Differential induction of antimicrobial REGIII by intestinal microbiota and Bifidobacterium breve NCC2950 査読有り

    Natividad MMJ, Hayes C, Motta J-P, Jury J, Galipeau HJ, Philip V, Rodenas CG, Kiyama H, Bercik P, and Verdu EF

    Appl Environ Microbiol   79 巻 ( 24 ) 頁: 7745-7754   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  58. Damage-induced neuronal endopeptidase is critical for presynaptic formation of neuro-muscular junctions 査読有り

    Nagata K, Kiryu-Seo S, Maeda M, Yoshida K, Morita T, Kiyama H

    J Neurosci.   30 巻 ( 20 ) 頁: 6954-6962   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  59. Neuronal injury-inducible gene is synergistically regulated by ATF3, cJun and STAT3 through the interaction with Sp1 in damaged neurons 査読有り

    Kiryu-Seo S, Kato R, Ogawa T, Nakagomi S, Nagata K, Kiyama H

    J Biol Chem   283 巻 ( 11 ) 頁: 6988-6996   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  60. Identification of peripherin as a novel Akt substrate in neurons 査読有り

    Konishi H, Namikawa K, Shikata K, Kobatake Y, Tachibana T, Kiyama H

    J Biol Chem   282 巻 ( 32 ) 頁: 23491-23499   2007年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  61. Pancreatitis-associated protein-III (PAP-III) is a novel macrophage chemoattractant implicated in nerve regeneration 査読有り

    Namikawa K, Okamoto T, Suzuki A, Konishi H, Kiyama H

    J Neurosci   26 巻 ( 28 ) 頁: 7460-7467   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  62. Unique anti-apoptotic activity of EAAC1 in injured motor neurons 査読有り

    Kiryu-Seo S, Gamo K, Tachibana T, Tanaka K, Kiyama H

    EMBO J   25 巻 ( 14 ) 頁: 3411-3421   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  63. Noxa is a critical mediator of p53-dependent motor neuron death after nerve injury in adult mouse. 査読有り

    Kiryu-Seo S, Hirayama T, Kato R, Kiyama H

    J Neurosci   25 巻 ( 6 ) 頁: 1442-1447   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  64. Expression of the Activating transcription factor 3 (ATF3) prevents JNK-induced neuronal death by promoting Hsp27 expression and Akt activation 査読有り

    Nakagomi S, Suzuki Y, Namikawa K, Kiryu-Seo S, Kiyama H

    J Neuosci   23 巻 ( 12 ) 頁: 5187-5196   2003年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  65. Akt / Protein kinase B prevents injury-induced motor neuron death and accelerates axonal regeneration 査読有り

    Namikawa K, Honma M, Abe K, Takeda M, Mansur K, Obata t, Miwa A, Okado H, Kiyama H

      20 巻   頁: 2875-2886   2000年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  66. Damage induced neuronal endopeptidase (DINE) is a unique metallopeptidase expressed in response to neuronal damage and activates superoxide scavengers. 査読有り

    Proc. Natl. Acad. Sci. USA   97 巻   頁: 4345-4350   2000年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  67. The small GTP-binding protein TC10 promotes growth cone-like formation and nerve elongation in neuronal cells, and its expression is induced during nerve regeneration in rats. 査読有り

    Tanabe K, Tachibana T, Yamashita T, Che YH, Yoneda Y, Ochi T, Tohyama M, Yoshikawa T, Kiyama H

      20 巻   頁: 4138-4144   2000年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  68. Accelerated nerve regeneration in mice by upregulated expression of IL-6 and IL-6 receptor after trauma. 査読有り

      183 巻   頁: 2627-2634   1996年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  69. p53 independent cyclin G expression in a group of mature neurons and its enhanced expression during nerve regeneration. 査読有り

    Morita N, Kiryu S, Kiyama H

      16 巻   頁: 5961-5966   1996年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  70. Nerve injury enhances rat neuronal glutamate transporter expression: identification by differential display PCR. 査読有り

    Kiryu S, Yao GL, Morita N, Kato H, Kiyama H

    J Neurosci.   15 巻   頁: 7872-7878   1995年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

▼全件表示

書籍等出版物 4

  1. 筋骨格系の解剖アトラス 上肢編

    木山博資、一柳雅仁( 担当: 監修)

    金芳堂  2020年4月  ( ISBN:ISBN978-4-7653-1818-1

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    総ページ数:262   記述言語:日本語 著書種別:教科書・概説・概論

  2. 人体の解剖生理学

    木山博資, 遠山正彌( 担当: 共編者(共編著者))

    金芳堂  2017年4月  ( ISBN:978-4-7635-1709-2

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    記述言語:日本語 著書種別:教科書・概説・概論

  3. 神経科学研究の最先端プロトコールI.分子組織化学

    塩坂貞夫(編集)木山博資(編集)( 担当: 編集)

    厚生社  1994年3月 

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    記述言語:日本語 著書種別:学術書

  4. バイオマニュアルシリーズ9「蛋白質核酸分子のin situ 同定法」

    遠山正彌、塩坂貞夫、木山博資( 担当: 共編者(共編著者))

    羊土社  1994年 

講演・口頭発表等 4

  1. A new horizon in nerve regeneration research -Consequences of interactions between neuron and non-neuronal cells in nerve regeneration- 招待有り 国際会議

    Kiyama H

    EURO-Japan International Workshop 

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    開催年月日: 2017年1月

    記述言語:英語   会議種別:口頭発表(基調)  

    開催地:Kyoto   国名:日本国  

  2. Lipids regulate microglial morphology and function 招待有り 国際会議

    Kiyama H

    Cold Spring Harbor Asia Conferences, Novel insights into Glia function & Dysfunction 

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    開催年月日: 2016年12月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    開催地:Suzhou, China   国名:日本国  

  3. The mitochondrial dynamics after nerve injury 招待有り 国際会議

    Kiryu-Seo S and Kiyama H

    25th International Society for Neurochemistry (ISN) 

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    開催年月日: 2015年8月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    開催地:Cairns Australia   国名:オーストラリア連邦  

  4. Microglia as a fate determinant of injured neurons invited speaker 招待有り 国際会議

    Kiyama H

    Cold Spring Harbor Asia Conferences 

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    開催年月日: 2015年6月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    開催地:Suzhou, China   国名:中華人民共和国  

科研費 6

  1. 慢性的なストレス負荷による新たなミクログリア作動原理の解明

    2013年4月 - 2015年3月

    科学研究費補助金 

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    担当区分:研究代表者 

  2. 脳内免疫担当細胞ミクログリアを主軸とする慢性難治性疼痛発症メカニズムの解明

    2011年4月 - 2015年3月

    科学研究費補助金  CREST

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    担当区分:研究分担者 

  3. 損傷神経再生における脂質リモデリングと脂質シグナリングの役割の解明

    研究課題/研究課題番号:19H03395  2019年4月 - 2022年3月

    科学研究費助成事業  基盤研究(B)

    木山 博資

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    担当区分:研究代表者 

    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    研究代表者が行ってきた損傷神経のバイオロジーの全体像の解明において、神経損傷による神経やグリアでの脂質の動態が不明であった。そこで本研究では、脂質分子や膜リモデリングが損傷後の神経再生や変性に与える影響やそのメカニズムを明らかにすることをめざす。本研究の成果は、神経変性疾患や損傷による運動機能の修復や神経障害性疼痛からの開放など出口戦略にむけ、治療法の開発にも新たな切り口を提供すると期待される。
    GPR34はG蛋白共役型受容体に属する細胞膜上に存在する受容体である。最近、リゾリン脂質の中でもリゾフォスファチジルセリンがリガンドであることが明らかになった。我々は遺伝子スクリーニングによりGPR34が脳内でミクログリア特異的に発現していることを同定し、神経障害により発現量が激増することを見出した。この脂質受容体の神経損傷における機能について同定するために、坐骨神経部分切断(L4切断)による疼痛モデルを用いて、疼痛行動におけるGPR34 の機能について検討した。GPR34 のノックアウトマウスを用いた実験では、神経損傷後に観察される脊髄後角でのミクログリアの増加やその活性化型の形態には変化が見られなかった。しかし、脊髄後角での炎症性サイトカイン(TNFalpha, IL-1beta, IL-6)の遺伝子発現は低下していた。さらにvon Freyテストにより疼痛行動を解析したところ、GPR34 ノックアウトマウスでは疼痛閾値の低下がみられた。以上のことからGPR34 を介したシグナルはミクログリアの増殖や形態変化には影響を及ぼさないが、炎症応答には関係しており、疼痛を惹起するシグナルと考えられた。次に野生型マウスの疼痛モデルを用いて、GPR34 のアンタゴニストを髄腔内に投与したところ、部分的に疼痛を抑制できることが示された。以前の研究と今回の結果を合わせて考察すると、神経損傷により生じるリゾフォスファチジスセリンはミクロクリアのGPR34 に作動して炎症性応答を増強し神経障害性疼痛を増悪していると考えられた。
    リゾフォスファチジルセリンの受容体であると考えられ、神経損傷後にミクログリアで発現が亢進するGPR34の機能が概ね明らかになった。また、コレステロールトランスポーターABCA1の機能解析の準備も順調に進んでいる。
    初年度は順調に進んでいることから、本年度も現状の研究計画を変更する予定はない。ただ、2020年度現時点 (4月24日時点)でCOVID-19の感染が拡大し、愛知県も感染拡大警戒地域に指定されており、不要不急の出勤等の自粛が求められていること、さらに研究や実験動物利用に制限がかかっていることなどから、本年度の研究においては停滞が懸念される。COVID-19状況次第では、愛知県や大学本部による研究等への制限の継続が長引くことが考えられ、その場合の遅滞は免れない。

  4. 損傷神経の生存軸索再生を制御するスクラップ&ビルドの分子基盤の解明

    研究課題/研究課題番号:17H05743  2017年4月 - 2019年3月

    新学術領域研究(研究領域提案型)

    木山 博資

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    担当区分:研究代表者 

    配分額:11050000円 ( 直接経費:8500000円 、 間接経費:2550000円 )

    昨年度はSiglec-Hが脳内のミクログリアにのみ発現し、脳常在性マクロファージには発現しないことを明らかにし、Siglec-Hの遺伝子にジフテリア毒素受容体を組み込んだマウスを用いることにより、ミクログリアを特異的に除去できることを示した。このノックインマウス(Siglec-H-DTR)では従来のIba1遺伝子やプロモーターを利用したミクログリア操作マウスよりはミクログリア特異性という点で優れている。これを用いることによりマクロファージとミクログリアの機能の違いやお互いの相互作用の研究に発展させることが可能になると考えられる。脳内ではミクログリアが主要な貪食能を有する細胞なので、ミクログリア自身がジフテリアトキシンによって細胞死に至った時に、どのようにしてミクログリアが除去(スクラップ)されるか検討した。脳内でミクログリアが特異的に障害されたとき、GFAPの発現上昇をともなってアストロサイトの活性化が観察された。また、ミクログリアの残骸がアストロサイトに貪食されている像も観察された。このことから、普段は貪食能を有しないアストロサイトが、ミクログリアが存在しない条件下では、代償的に貪食能を発揮することが明らかになった。このような代償性貪食が、より生理的な条件下でも生じるかどうかは検討中である。現時点ではアストロサイトの代償性貪食機能の作動機序は不明であるが、アストロサイトには従来から知られている機能に加え、新たにスクラッパーとしての機能が存在することが示された。
    平成30年度が最終年度であるため、記入しない。
    平成30年度が最終年度であるため、記入しない。

  5. 損傷神経の運命決定におけるオルガネラダイナミクス

    研究課題/研究課題番号:16H05117  2016年4月 - 2019年3月

    木山 博資

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    担当区分:研究代表者 

    配分額:17550000円 ( 直接経費:13500000円 、 間接経費:4050000円 )

    本研究では、オルガネラ動態と損傷神経の運命の関係を明らかにし、その動態を決定する分子機序に迫ることをめざした。神経損傷特異的なプロモーター下でミトコンドリア(Mt)を標識し、かつCre蛋白を発現するトランスジェニック動物(TG)を用い損傷神経内のMt等の動態を明らかにした。軸索損傷により、軸索内のMtは分裂小型化し、速い速度で移動した。再生軸索先端へより多くのMtを輸送するためと考えられる。Mtの分裂を担っているDrp1分子を損傷運動神経特異的にノックアウトすると、Mtには多様な変調が生じ細胞死が加速した。Mtの分裂能は神経細胞の生存に必要な応答であることが明らかになった。
    運動神経損傷後に生じるオルガネラ動態の変化が、損傷神経細胞の生存や再生に重要な役割を果たしていることが明らかになった。特にミトコンドリアは融合と分裂を繰り返すことで機能を維持しているが、分裂の欠損により神経損傷に対する耐性が失われることが明らかになった。これらの結果は、オルガネラ動態の異常に起因する神経変性疾患の変性メカニズムの解明に繋がることが予想され、これら疾患の治療法開発への貢献が期待される。本研究の成果は、神経変性疾患以外にも外傷後の運動神経再生や神経障害性疼痛の治療法開発にも新たな知見を提供すると考えられる。

  6. 慢性ストレスにおける固有感覚異常が惹起する異常疼痛発症メカニズムの解明

    研究課題/研究課題番号:16K15170  2016年4月 - 2018年3月

    木山 博資

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    担当区分:研究代表者 

    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    線維筋痛症や慢性疲労症候群(CFS)で見られる慢性疼痛発症メカニズムを明らかにするために、慢性ストレスを負荷するラットCSFモデルを用い検討した。このモデルではストレス負荷後に慢性的異常疼痛が見られる。ストレス負荷開始後、まず後根神経節の固有感覚ニューロンの過活動が生じ、次に脊髄後角の内側部でのミクログリアの活性化、さらに前角背側部の運動ニューロン周辺にミクログリアの活性化が認められた。これらの活性化が見られる領域は脊髄の反射弓に沿っており、抗重力筋などの無意識下の緊張の持続が反射弓の過活動を惹起し、それに沿った領域でミクログリアが活性化し、それが疼痛の記憶となっていることが示唆された。

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担当経験のある科目 (本学) 17

  1. 人体器官の構造(組織学)講義・実習

    2021

  2. 人体器官の構造(肉眼解剖学)講義・実習

    2021

  3. 基礎医学セミナー

    2021

  4. 機能組織学セミナー

    2021

  5. 機能組織学実験研究

    2021

  6. 修士講義

    2021

  7. 医工連携セミナー

    2021

  8. 人体器官の構造(組織学)講義・実習

    2019

  9. 修士講義

    2019

  10. 基礎セミナーA

    2019

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    ゼミ形式

  11. 基礎医学セミナー

    2019

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    医学研究法の指導、論文作成

  12. 神経解剖学

    2019

  13. 人体器官の構造(肉眼解剖学)講義・実習

    2019

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    講義と実習

  14. 基礎セミナーA

    2015

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    ゼミ形式

  15. 自然環境と人間

    2015

  16. 基礎セミナーA

    2012

  17. 基礎セミナーB

    2011

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社会貢献活動 6

  1. J Neurochemistry (Handling Editor)

    2000年10月 - 2013年12月

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    Handling Editor

  2. J Chemical Neuroanatomy (Editor)

    2013年10月 - 現在

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    編集委員 Editor

  3. Anatomical Science International (Managing Editor)

    2015年4月 - 現在

  4. 自律神経 (編集委員)

    2013年1月 - 現在

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    雑誌「自律神経」編集委員

  5. 人体解剖トレーニングセミナー  実行委員長

    2011年8月 - 現在

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    医育機関の解剖教育担当者の解剖トレーニング
    実行委員長

  6. 中学校講演会

    2013年11月

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    富山市立山室中学で生徒父兄対象に講演した。

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