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障害モデル研究部門

1 研究活動の概要・目的

障害モデル研究部は、新たに明らかにされた遺伝性疾患のモデル動物の作製を行う障害モデル作製開発研究室と、作製されたモデル動物の障害の解析と治療法の評価を行う障害モデル解析応用研究室から構成されます。
知的障害、てんかん、自閉症スペクトラム障害などの神経疾患の症例から新たに明らかになった原因遺伝子に相当する遺伝子を改変したモデルマウスの作製や、疾患モデルマウスの詳細な病態解析と治療法探索を行い、将来患者に還元できる新しい事実や解釈を得ることを研究活動の目的としています。目的を達成するため、マウス、ラット、ウサギを用いた動物実験、動物組織の染色や診断、細胞培養、生化学的分析や遺伝子分析、電気生理学実験等を行っています。

2 研究内容紹介

胎児後期から新生児期に発生した異常によって脳性麻痺、精神発達遅滞、運動障害、てんかんなどの脳障害が起こることを周生期(周産期)脳障害と呼び、この疾患原因を探り治療法を開発する研究を障害モデル研究部の前身である周生期学部は行っていました。昭和47年に発達障害研究所が設立された当時、周生期脳障害害の原因の大部分は分娩に伴うものだろうと考えられてきました。
しかし近代的麻酔により帝王切開が安全に行われるようになって平成7年頃までに新生児仮死の多くを防ぐことができるようになったのに周生期脳障害は減少しませんでした。この歴史的事実は周生期脳障害のほとんどの原因は分娩より前に決まっていることを示唆しています。
近年になって安価で高速度の次世代シークエンスが患者ゲノムを網羅的に探索し始めると、出生前後の環境に原因があると長らく信じられていた脳性麻痺患者の半数程度に遺伝子変異があるという報告もされました。さらに次世代シークエンスは、両親からの遺伝だけでなく両親には無い異常が精子や卵子に新しく生じた遺伝子異常が多くの脳障害を引き起こすことも明らかにしてきました。
このような時代背景にあり、障害モデル研究部は周生期学部が行っていた周生期脳障害の研究を引き継ぐだけでなく、さらに周生期脳障害と呼ばれてきた疾患のかなりの原因を占めると思われる遺伝的な原因がどう脳障害に進展するかを特に深く調べています。
ここ数年は主に、@ルビンスタイン・テイビ症候群のモデルマウスであるCBP遺伝子変異に関する研究、Aラットモデルを用いた臍帯血移植や低酸素虚血性脳症治療の研究、B少歯症原因遺伝子の神経細胞への影響の研究、CPEHO症候群のモデルマウスであるGirdin遺伝子変異に関する研究を行っています。この他、同じ棟にある中央病院と共同で重症心身障害患者に新しく見つかった遺伝子変異と症状を関連づけする努力も続けています。

3 メンバー紹介

部長 浅井 真人(あさい まさと)(https://researchmap.jp/read0077659/)
主任研究員 時田 義人(ときた よしひと)(https://researchmap.jp/read0006827/)
主任研究員 高木 豪(たかぎ つよし)(https://researchmap.jp/modelanimal/)
研究員 飯田 真智子(いいだ まちこ)(https://researchmap.jp/machikoi/)
研究員 田中 基樹(たなか もとき)(https://researchmap.jp/read0153211/)
研究員 吉崎 嘉一(よしざき かいち)(https://researchmap.jp/7000017751/)
客員研究者 東 雄二郎(ひがし ゆうじろう)(https://researchmap.jp/read0042826/)
客員研究者 中西 圭子(なかにし けいこ)(https://researchmap.jp/read0006834/)
リサーチレジデント 欠員中
研究助手 水谷 友香(みずたに ゆか)
(胚操作・獣医師)

4 活動内容

トピックス

2019年3月
新しく障害モデル研究部門としてスタートしました

5 研究業績←クリックで表示

2018

Tanaka M1, Ogaeri T1, Samsonov M2, Sokabe M1 (1Nagoya Univ, 2R-Pharm): Nestorone exerts long-term neuroprotective effects against transient focal cerebral ischemia in adult male rats. Brain Res: doi: 10.1016/j.brainres.2018.09.022, 2018 [Epub ahead of print].

Tanaka M1, Ogaeri T1, Samsonov M2, Sokabe M1 (1Nagoya Univ, 2R-Pharm): Progesterone improves functional outcomes after transient focal cerebral ischemia in both aged male and female rats. Exp Gerontol 113: 29-35, 2018.

Tanaka M1, Ogaeri T1, Samsonov M2, Sokabe M1 (1Nagoya Univ, 2R-Pharm): The 5α-Reductase Inhibitor Finasteride Exerts Neuroprotection Against Ischemic Brain Injury in Aged Male Rats. Transl Stroke Res 10: 67-77, 2018.

Kobayashi K1, Takagi T, Ishii S2, Suzuki H1, Miyakawa T3 (1Nippon Med Sch, 2RIKEN, 3Fujita Health Univ): Attenuated bidirectional short-term synaptic plasticity in the dentate gyrus of Schnurri-2 knockout mice, a model of schizophrenia. Mol Brain 11: 56, 2018

Nakanishi K, Niida H1,2, Tabata H, Ito T1, Hori Y1, Hattori M1, Johmura Y1,3, Yamada C1, Ueda T1, Takeuchi K4, Yamada K, Nagata K-I, Wakamatsu N, Kishi M5, Pan YA6, Ugawa S1, Shimada S1,7, Sanes JR8, Higashi Y, Nakanishi M1,3. (1Nagoya City Univ, 2Hamamatsu Univ Sch Med, 3IMS, Univ Tokyo, 4Aichi Med Univ, 5Nozaki Tokushukai Hosp, 6Virginia Tech Carilion Res Inst, 7Osaka Univ Grad Sch Med, 8Harvard Univ) Isozyme specific role of SAD-A in neuronal migration during development of cerebral cortex. Cerebral Cortex 2018, Oct 11. DOI: 10.1093/cercor/bhy253 [Epub ahead of print]

Sato Y1, Kondo T1, Ueda K1, Hattori T1, Mikrogeorgiou A1, Sugiyama Y1, Suzuki T1, Yamamoto M2, Hirata H2, Hirakawa A3, Nakanishi K, Tsuji M4, Hayakawa M1. (1Nagoya Univ Hosp, 2Nagoya Univ, 3Univ Tokyo,4NCCC) Administration of Bone Marrow-Derived Mononuclear Cells Contributed to the Reduction of Hypoxic-Ischemic Brain Injury in Neonatal Rats. Front. Neurol, 30 November 2018, DOI: 10.3389/fneur.2018.00987

Hagihara H1, Catts VS2, Katayama Y3, Shoji H1, Takagi T. Huang FL4, Nakao A1, Mori Y5, Huang KP4, Ishii S6, Graef IA7, Nakayama KI3, Weickert SC2, Miyakawa T1 (1Fujita Health Univ, 2 Univ New South Wales, 3Kyusyu Univ, 4Kyoto Univ, 5NIH, 6RIKEN, 7Stanford Univ): Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders. Neuropsychopharmacology 43: 459-468, 2018.

Weng L1, Han YP1, Enomoto A1, Kitaura Y1, Nagamori S2, Kanai Y3, Asai N1, An J1, Takagishi M1, Asai M, Mii S1, Masuko T4, Shimomura Y1, Takahashi M1 (1Nagoya Univ, 2Nara Medical Univ, 3Osaka Univ, 4Kindai Univ): Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex. PLoS Biol 16: e2005090, 2018.

Mizutani Y, Kuga D1, Iida M, Ushida K2, Takagi T, Tokita Y, Takahashi M2, Asai M (1Anjo Kosei Hosp 2Nagoya Univ): Use of Anti-phospho-girdin Antibodies to Visualize Intestinal Tuft Cells in Free-Floating Mouse Jejunum Cryosections. J Vis Exp 21: 133, 2018.

Saito K, Takahashi K1, Huang B2, Asahara M3, Kiso H1, Togo Y1, Tsukamoto H1, Mishima S1, Nagata M4, Iida M, Tokita Y, Asai M, Shimizu A1, Komori T5, Harada H6, MacDougall M7, Sugai M8, Bessho K1 (1Kyoto Univ, 2Charles Sturt Univ, 3Aichi Gakuin Univ, 4Niigata Univ, 5Nagasaki Univ, 6Iwate Med Univ, 7Univ of British Columbia, 8Univ of Fukui): Loss of Stemness, EMT, and Supernumerary Tooth Formation in Cebpb(-/-)Runx2(+/-) Murine Incisors. Sci Rep 8: 5169, 2018.

Yajima I1, Ahsan N2, Akhand AA2, Yoshinaga M1, Ohgami N1, Iida M, Oshino R1, Naito M1, Wakai K1, Kato M1 (1Nagoya Univ, 2Univ Dhaka): Arsenic levels in cutaneous appendicular organs are correlated with digitally evaluated hyperpigmented skin of the forehead but not the sole in Bangladesh residents. J Expo Sci Environ Epidemiol 28: 64-68, 2018.

Ninomiya H1, Ohgami N1, Oshino R1, Kato M2, Ohgami K1, Li X1, Shen D1, Iida M, Yajima I1, Angelidis CE3, Adachi H4, Katsuno M1, Sobue G1, Kato M1 (1Nagoya Univ, 2Nagoya Inst of Tech, 3Univ Ioannina, 4Univ Occupational and Environmental Health Sch Med): Increased expression level of Hsp70 in the inner ears of mice by exposure to low frequency noise. Hear Res 363: 49-54, 2018.

Yoshinaga M1, Ninomiya H1, Al Hossain MMA1, Sudo M1, Akhand AA2, Ahsan N2, Alim MA3, Khalequzzaman M4, Iida M, Yajima I1, Ohgami N1, Kato M1(1Nagoya Univ, 2Univ Dhaka, 3 Directorate General of Health Services, 4 Bangabandhu Sheikh Mujib Med Univ): A comprehensive study including monitoring, assessment of health effects and development of a remediation method for chromium pollution. Chemosphere 201: 667-675, 2018.

2017

MikrogeorgiouA1, SatoY1, KondoT1, HattoriT1, SugiyamaY1, ItoM1, SaitoA1, NakanishiK, TsujiM2, KazamaT3, KanoK3, MatsumotoT3, HayakawaM1. (1Nagoya Univ Hosp, 2NCCC, 3Nihon Univ) Dedifferentiated fat cells, as a novel source for cell therapy to target neonatal hypoxic ischemic encephalopathy. Dev Neurosci 39:273-286, 2017. DOI: 10.1159/000455836

Nakao A1, Miyazaki N2, Ohira K3, Hagihara H1, Takagi T, Usuda N1, Ishii S4, Murata K2, Miyakawa T1 (1Fujita Health Univ, 2NIPS, 3Mukogawa Women’s Univ, 4RIKEN): Immature morphological properties in subcellular-scale structures in the dentate gyrus of Schnurri-2 knockout mice: a model for schizophrenia and intellectual disability. Mol Brain 10: 60, 2017.

Zhang R1, Asai M, Mahoney CE1, Joachim M1, Shen Y1, Gunner G1, Majzoub JA1 (1Harvard Med Sch): Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice. Mol Psychiatry 22: 733-744, 2017.

Kuga D1, Ushida K1, Mii S1, Enomoto A1, Asai N1, Nagino M1, Takahashi M1, Asai M (1Nagoya Univ): Tyrosine Phosphorylation of an Actin-Binding Protein Girdin Specifically Marks Tuft Cells in Human and Mouse Gut. J Histochem Cytochem 65: 347-366, 2017.

Machida J1, Goto H1, Tatematsu T1, Shibata A2, Miyachi H1, Takahashi K3, Izumi H4, Nakayama A, Shimozato K1, Tokita Y (1Aichi Gakuin Univ, 2Ogaki Municipal Hosp,3Kyoto Univ, 4 Univ of Occupational and Environmental Health): WNT10A variants isolated from Japanese patients with congenital tooth agenesis. Hum Genome Var 4: 17047, 2017.

Li X1, Ohgami N1, Omata Y1, Yajima I1, Iida M, Oshino R1, Ohnuma S1, Ahsan N2, Akhand AA2, Kato M1 (1Nagoya Univ, 2Univ Dhaka): Oral exposure to arsenic causes hearing loss in young people aged 12-29 years and in young mice. Sci Rep 7: 6844, 2017.

Kumasaka MY1, Yajima I1, Ohgami N1, Ninomiya H1, Iida M, Li X1, Oshino R1, Tanihata H1, Yoshinaga M1, Kato M1 (1Nagoya Univ): Manganese-Mediated Decrease in Levels of c-RET and Tyrosine Hydroxylase Expression In Vitro. Neurotox Res 32: 661-670, 2017.

Yajima I1, Kumasaka MY1, Iida M, Oshino R1, Tanihata H1, Hossain AA1, Ohgami N1, Kato M1 (1Nagoya Univ): Arsenic-mediated hyperpigmentation in skin via NF-kappa B/endothelin-1 signaling in an originally developed hairless mouse model. Arch Toxicol 91: 3507-3516, 2017.

Goto H1, Machida J1, Shibata A1, Tatematsu T1, Osumi E2, Miyachi H1, Takahashi K3, Nakayama A, Higashi H, Nagao T2, Shimozato K1, Tokita Y (1Aichi-Gakuen Univ, 2Okazaki City Hosp, 3Kyoto Univ): Novel RUNX2/CBFA1 mutation in the runt domain in a Japanese patient with cleidocranial dysplasia. J Oral and Maxillofac Surg Med and Pathol 29: 222-224, 2017.

Muramatsu Y1, Tokita Y, Mizuno S2, Nakamura M (1Nagoya Univ, 2Central Hosp): Disparities in visuo-spatial constructive abilities in Williams syndrome patients with typical deletion on chromosome 7q11.23. Brain Dev 39: 145-153, 2017.

NakanishiK, SatoY1, MizutaniY, ItoM1, HirakawaA2, Higashi Y (1Nagoya Univ, 2Nagoya Univ Hospital): Rat umbilical cord blood cells attenuate hypoxic-ischemic brain injury in neonatal rats. Sci Rep 7: 44111, 2017.

2016

Johmura Y1, Yamashita E1, Shimada M1, Nakanishi K, Nakanishi M1 (1Nagoya City Univ): Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation. Sci Rep 6: 31194, 2016.

Menuchin-Lasowski Y1, Oren-Giladi P1, Xie Q2, Ezra-Elia R3, Ofri R3, Peled-Hajaj S1, Farhy C1, Higashi Y, Van de Putte4, T, Kondoh H5, Huylebroeck D4, Cvekl A2, Ashery-Padan R1 (1Tel-Aviv Univ. 2Albert Einstein College of Med, 3Hebrew Univ of Jerusalem, 4KU Leuven, 5Kyoto Sangyo Univ): Sip1 regulates the generation of the inner nuclear layer retinal cell lineages in mammals. Development 143: 2829-2841, 2016.

Ohayon D1, Garces A1, Joly W1, Soukkarieh C1, Takagi T, Sabourin JC1, Agius E2, Darling DS3, De Santa Barbara P4, Higashi Y, Stolt CC5, Hugnot JP1, Richardson WD6, Carroll P1, Pattyn A1 (1INSERM, 2Univ de Toulouse, 3Univ of Louisville, 4Univ of Montpelier, 5Universitat Erlangen-Numberg, 6Univ college London): Onset of Spinal Cord Astrocyte Precursor Emigration from the Ventricular Zone Involves the Zeb1 Transcription Factor. Cell Rep 17: 1473-1481, 2016.

Rasouly HM1, Kumar S1, Chan S1, Pisarek-Horowitz A1, Sharma R1, Xi QJ2, Nishizaki Y, Higashi Y, Salant DJ1, Maas RL2, Lu W1 (1BostonUniv Sch of Med, 2Harvard Med Sch): Loss of Zeb2 in mesenchyme-derived nephrons causes primary glomerulocystic disease. Kidney Int 90: 1262-1273, 2016.

Shimada M1, Goshima T1, Matsuo H1, Johmura Y1, Haruta M1, Murata K1, Tanaka H2, Ikawa M3, Nakanishi K, Nakanishi M1 (1Nagoya City Univ, 2Nagasaki International Univ, 3Osaka Univ): Essential role of auto-activation circuitry on Aurora B-mediated H2AX-pS121 in mitosis. Nat Commun 7: 12059, 2016.

Wu X1, Briseno CG1, Grajales-Reyes GE1, Haldar M1, Iwata A1, Kretzer, NM1, Kc W1, Tussiwand R1, Higashi Y, Murphy TL1, Murphy KM1 (1Washington Univ): Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate. Proc Natl Acad Sci USA 113: 14775-14780, 2016.

Shibata A1, Machida J1, Yamaguchi S1, Kimura M1, Tatematsu T1, Miyachi H1, Matsushita M2,Kitoh H2, Ishiguro N2, Nakayama A, Higashi Y, Shimozato K1, Tokita Y (1Aichi-Gakuin Univ, 2Nagoya Univ): Characterization of novel RUNX2 mutation with alanine tract expansion from Japanese cleidocranial dysplasia patient. Mutagenesis 31: 61-7, 2016. doi:?10.1093/mutage/gev057.

Yasumi T1, Inoue M1, Maruhashi M1, Kamachi Y1, Higashi Y, Kondoh H2, Uchikawa M1 (1Osaka Univ, 2Kyoto Sangyo Univ): Regulation of trunk neural crest delamination by δEF1 and Sip1 in the chicken embryo. Dev Growth Differ. 58:155?237, 2016.

Johmura Y1, Sun J1, Kitagawa K2, Nakanishi K, Kuno T1, Naiki-Ito A1, Sawada Y1, Miyamoto T1, Okabe A3, Aburatani H3, Li S-F4, Miyoshi I1, Takahashi S1, Kitagawa M2, Nakanishi M1 (1Nagoya City Univ, 2Hamamatsu Univ, 3Univ of Tokyo, 4Dalian Univ) : SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence. Nat Commun 7:10574, 2016. Doi: 10.1038/ncomms10574.

2015

Takagi T, Nishizaki Y, Matsui F, Wakamatsu N, Higashi Y: De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome. Hum Mol Genet. 24:6390-402, 2015.

Omilusik KD1, Best JA1, Yu B1, Goossens S2, Weidemann A3, Nguyen JV1, Seuntjens E4, Stryjewska A4, Zweier C5, Roychoudhuri R5, Gattinoni L5, Bird LM5, Higashi Y, Kondoh H6, Huylebroeck D4, Haigh J2, Goldrath AW1 (1Univ of California, 2Monash Univ, 3Friedrich-Alexander Univ, 4KU Leuven, 5NIH, 6Kyoto Sangyo Univ): Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection. J Exp Med. 212:2027-2039, 2015.

Choi JK1, Zhu A1, Jenkins BG1, Hattori S2, Kil KE1, Takagi T, Ishii S3, Miyakawa T2, Brownell AL1 (1Harvard Medical School, 2Fujita Health Univ, 3RIKEN) : Combined behavioral studies and in vivo imaging of inflammatory response and expression of mGlu5 receptors in schnurri-2 knockout mice. Neurosci Lett 609: 159-164, 2015.

Shinagawa T1, Huynh LM1, Takagi T, Tsukamoto D1, Tomaru C1, Kwa HG1, Dohmae N1, Noguchi J2 and Ishii S1 (1RIKEN, 2NIAS): Disruption of Th2a and Th2b genes causes defects in spermatogenesis. Development 142: 1287-92, 2015.

Tatematsu T1, Kimura M1, Nakashima M2, Machida J1, Yamaguchi S1, Shibata A1, Goto H1, Nakayama A, Higashi H, Miyachi H1, Shimozato K1, Matsumoto N2, Tokita Y (1Aichi-Gakuin Univ, 2Yokohama City Univ): An aberrant splice acceptor site due to a novel intronic nucleotide substitution in MSX1 gene is the cause of congenital tooth agenesis in a Japanese family. PLOSONE, 10(6): e0128227, 2015. doi: 10.1371/journal.pone.0128227.

2014

Machida J1, Nishiyama T2, Kishino H3, Yamaguchi S1, Kimura M1, Shibata A1, Tatematsu T1, Kamamoto M1, Yamamoto K1, Makino S1, Miyachi H1, Shimozato K1,Tokita Y. (1Aichi-Gakuin Univ, 2Aichi Medical Univ, 3Univ of Tokyo)  Genetic Epidemiology of Tooth Agenesis in Japan: A Population-and Family-based Study. Clin Genet DOI:?10.1111/cge.12456. 2014

Yamaguchi S1, Machida J1, Kamamoto M1, Kimura M1, Shibata A1, Tatematsu T1, Miyachi H1, Higashi Y, Jezewski PA2, Nakayama A, Shimozato K1,Tokita Y. (1Aichi-Gakuin Univ, 2Univ of Alabama) Characterization of novel MSX1 mutations identified in Japanese patients with nonsyndromic tooth agenesis. PLOSONE 9, e102944. DOI: 10.1371/journal.pone.0102944. 2014

Kimura M1, Tokita Y, Machida J1, Shibata A1, Tatematsu T1, Tsurusaki Y2, Miyake M2, Saitsu H2, Miyachi H1, Shimozato K1, Matsumoto N2, Nakashima M2. (1Aichi-Gakuin Univ, 2Yokohama City Univ) A Novel PITX2 Mutation Causing Iris Hypoplasia. Hum Genome Variation 1, Article number: 14005. DOI: 10.1038/hgv.2014.5. 2014

Shinagawa T1, Takagi T, Tsukamoto D1, Tomaru C1, Huynh LM1, Sivaraman P1, Kumarevel T1, Inoue K1, Nakato R2, Katou Y2, Sado T3, Takahashi S4, Ogura A1, Shirahige K2, Ishii S1 (1RIKEN, 2Tokyo Univ, 3Kyusyu Univ, 4Tsukuba Univ): Histone variants enriched in oocytes enhance reprogramming to induced pluripotent stem cells. Cell Stem Cell 14 : 217-27, 2014.

Hattori T1, Sato Y1, KondoT1, Ichinohashi Y1, Sugiyama Y1, Yamamoto M1, Kotani T1, Hirata H1, HirakawaA1, Suzuki S1, Tsuji M2, Ikeda T3, Nakanishi K, KojimaS1, Blomgren K4, Hayakawa M1. (1Nagoya Univ, 2NCVC, 3Mie Univ, 4Karolinska Inst) Administration of umbilical cord blood cells transiently decreased hypoxic?ischemic brain injury in neonatal rats. Dev Neurosci 37: 95-104, 2015