{"created":"2023-05-15T15:17:00.816659+00:00","id":3016,"links":{},"metadata":{"_buckets":{"deposit":"9ee3d83f-a641-43cf-97ea-a6eb62501277"},"_deposit":{"created_by":12,"id":"3016","owners":[12],"pid":{"revision_id":0,"type":"depid","value":"3016"},"status":"published"},"_oai":{"id":"oai:obihiro.repo.nii.ac.jp:00003016","sets":["242:243"]},"author_link":["178","318","23","5370"],"item_6_alternative_title_1":{"attribute_name":"その他（別言語等）の研究課題名","attribute_value_mlt":[{"subitem_alternative_title":"Attempt to develop animal model for the formation of paired helical filaments in the brains of Alzheimer's disease patients via sustained inactivation of integrin-linked kinase in mouse brain.","subitem_alternative_title_language":"en"}]},"item_6_contributor_5":{"attribute_name":"研究分担者","attribute_value_mlt":[{"contributorNames":[{"contributorName":"宮沢, 孝幸","lang":"ja"}],"nameIdentifiers":[{"nameIdentifier":"5370","nameIdentifierScheme":"WEKO"},{"nameIdentifier":"80282705","nameIdentifierScheme":"e-Rad","nameIdentifierURI":"https://kaken.nii.ac.jp/ja/search/?qm=80282705"}]},{"contributorAffiliations":[{"contributorAffiliationNameIdentifiers":[{"contributorAffiliationScheme":"ISNI","contributorAffiliationURI":"http://www.isni.org/isni/"}],"contributorAffiliationNames":[{"contributorAffiliationNameLang":"ja"}]}],"contributorNames":[{"contributorName":"Furuoka, Hidefumi","lang":"en"},{"contributorName":"古岡, 秀文","lang":"ja"}],"familyNames":[{"familyName":"Furuoka","familyNameLang":"en"},{"familyName":"古岡","familyNameLang":"ja"}],"givenNames":[{"givenName":"Hidefumi","givenNameLang":"en"},{"givenName":"秀文","givenNameLang":"ja"}],"nameIdentifiers":[{"nameIdentifier":"23","nameIdentifierScheme":"WEKO"},{"nameIdentifier":"1000060238665","nameIdentifierScheme":"CiNii ID","nameIdentifierURI":"http://ci.nii.ac.jp/nrid/1000060238665"},{"nameIdentifier":"60238665","nameIdentifierScheme":"e-Rad","nameIdentifierURI":"https://kaken.nii.ac.jp/ja/search/?qm=60238665"},{"nameIdentifier":"read0167488","nameIdentifierScheme":"researchmap","nameIdentifierURI":"https://researchmap.jp/read0167488"}]},{"contributorAffiliations":[{"contributorAffiliationNameIdentifiers":[{"contributorAffiliationNameIdentifier":"","contributorAffiliationScheme":"ISNI","contributorAffiliationURI":"http://www.isni.org/isni/"}],"contributorAffiliationNames":[{"contributorAffiliationName":"","contributorAffiliationNameLang":"ja"}]}],"contributorNames":[{"contributorName":"Nishimura, Masakazu","lang":"en"},{"contributorName":"西村, 昌数","lang":"ja"}],"familyNames":[{"familyName":"Nishimura","familyNameLang":"en"},{"familyName":"西村","familyNameLang":"ja"}],"givenNames":[{"givenName":"Masakazu","givenNameLang":"en"},{"givenName":"昌数","givenNameLang":"ja"}],"nameIdentifiers":[{"nameIdentifier":"178","nameIdentifierScheme":"WEKO"},{"nameIdentifier":"9000005514215","nameIdentifierScheme":"CiNii ID","nameIdentifierURI":"http://ci.nii.ac.jp/nrid/9000005514215"},{"nameIdentifier":"50011995","nameIdentifierScheme":"e-Rad","nameIdentifierURI":"https://kaken.nii.ac.jp/ja/search/?qm=50011995"},{"nameIdentifier":"read0167489","nameIdentifierScheme":"researchmap","nameIdentifierURI":"https://researchmap.jp/read0167489"}]}]},"item_6_description_10":{"attribute_name":"研究代表者番号","attribute_value_mlt":[{"subitem_description":"50264809","subitem_description_type":"Other"}]},"item_6_description_11":{"attribute_name":"研究機関","attribute_value_mlt":[{"subitem_description":"帯広畜産大学","subitem_description_language":"ja","subitem_description_type":"Other"}]},"item_6_description_13":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"インテグリンリンクドキナーゼ(ILK)の遺伝子操作により神経原線維変化をマウス脳に形成させることで、アルツハイマー病などの神経変性疾患で確認される神経脱落像ならびにそれに基づく神経活動の異常に即した病態を忠実に再現した動物モデルの作製を試みた。ILKの活性不活化変異体(DN-ILK)を3週間にわたり導入発現した急性期マウスの海馬では、ILK酵素活性の有意な低下が認められ、それに伴い神経原線維変化病変に高頻度に出現するタウタンパク質のSer^<199>とSer^<202>の異常リン酸化量ならびにそれらを触媒するGSK-3βの活性型(Tyr^<216>-p)が増加した。ところが、12週後の慢性期になると、内在ILKの発現が誘導され、ILKならびGSK-3βの酵素活性が正常レベルにまで回復するとともに、急性期で認められたタウの異常リン酸化量の増加も回復した。DN-ILKを発現したマウス海馬では、生理機能を維持するため内在ILKの発現誘導を促進する適応機構が生じ、ILKならびGSK-3βの酵素活性を正常レベルにまで回復させ、タウタンパク質の機能を維持していることが示唆された。このように、培養細胞の場合とは異なりin vivoの動物個体では、長期間ILK活性を阻害したことに起因する代償機構が出現するため、神経原線維変化の発生には至らず、病態モデルを完成することが出来なかった。今後、ILK酵素活性を阻害した場合に生じる代償機構の詳細を解明し、それら適応機序を阻止する方法を見出すことが出来れば、ILKの遺伝子操作により神経原線維変化の動物モデルを作製することが十分可能でると考える。一方、逆の視点から見れば、アルツハイマー病の初期では、ILKの活性を高める薬物の投与が神経原線維変化の進行阻止に有効である可能性を強く示唆している。","subitem_description_language":"ja","subitem_description_type":"Abstract"},{"subitem_description":"Integrin-linked kinase (ILK) is a focal adhesion serin/threonine protein kinase with an important role in integrin and growth factor signaling pathways. Recently, we demonstrated that ILK inactivation results in aberrant tau phosphorylation, which is identical to some of the aberrant phosphorylation sites in paired helical filaments in the brains of patients with Alzheimer's disease, via sustained activation of GSK-3β in cultured N1E-115 cells. In this study, we examined whether sustained inactivation of ILK leads to aberrant tau phosphorylation and produces paired helical filaments in mouse brain. Transfection and expression of a kinase-deficient mutant of ILK (DN-ILK), which behaves as a dominant negative, to mouse brain in vivo lead to inhibition of ILK activity and increase in active form of GSK-3β, and then induce aberrant tau phosphorylation in the hippocampus 3 wk after the transfection. However, the inhibition of endogenous ILK activity induced by DN-ILK is not retained and recovered to the basal level via a marked increase of endogenous ILK protein 12 wk after DN-ILK transfection. This compensatory mechanism leads the active form of GSK-3β to normal level and results in a decrease in the levels of aberrant tau phosphorylation. These results strongly suggest that ILK protects against aberrant tau phosphorylation via inhibition of GSK-3β activity in vivo. Although we could not create the mouse model for paired helical filaments in the brains of patients with Alzheimer's disease, our results imply that medical drugs to activate ILK activity might be effective in the therapy of patients with the early stage of Alzheimer's disease. Further studies are required to elucidate the compensatory mechanism after ILK inactivation in the brain.","subitem_description_language":"en","subitem_description_type":"Abstract"}]},"item_6_description_14":{"attribute_name":"内容記述","attribute_value_mlt":[{"subitem_description":"平成16年度～平成18年度科学研究費補助金基盤研究(B)研究成果報告書","subitem_description_language":"ja","subitem_description_type":"Other"}]},"item_6_description_19":{"attribute_name":"フォーマット","attribute_value_mlt":[{"subitem_description":"application/pdf","subitem_description_type":"Other"}]},"item_6_description_9":{"attribute_name":"研究課題番号","attribute_value_mlt":[{"subitem_description":"16380195","subitem_description_type":"Other"}]},"item_6_text_12":{"attribute_name":"助成元","attribute_value_mlt":[{"subitem_text_language":"ja","subitem_text_value":"科学研究費助成事業"}]},"item_6_version_type_20":{"attribute_name":"著者版フラグ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_970fb48d4fbd8a85","subitem_version_type":"VoR"}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2018-01-30"}],"displaytype":"detail","filename":"H19ishii.pdf","filesize":[{"value":"1.6 MB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"H19ishii.pdf","url":"https://obihiro.repo.nii.ac.jp/record/3016/files/H19ishii.pdf"},"version_id":"7d801529-e8f0-45af-a1f4-279448ede369"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_researcher":{"attribute_name":"研究代表者","attribute_type":"creator","attribute_value_mlt":[{"creatorAffiliations":[{"affiliationNameIdentifiers":[{"affiliationNameIdentifier":"","affiliationNameIdentifierScheme":"ISNI","affiliationNameIdentifierURI":"http://www.isni.org/isni/"}],"affiliationNames":[{"affiliationName":"","affiliationNameLang":"ja"}]}],"creatorNames":[{"creatorName":"Ishii, Toshiaki","creatorNameLang":"en"},{"creatorName":"石井, 利明","creatorNameLang":"ja"}],"familyNames":[{"familyName":"Ishii","familyNameLang":"en"},{"familyName":"石井","familyNameLang":"ja"}],"givenNames":[{"givenName":"Toshiaki","givenNameLang":"en"},{"givenName":"利明","givenNameLang":"ja"}],"nameIdentifiers":[{"nameIdentifier":"318","nameIdentifierScheme":"WEKO"},{"nameIdentifier":"9000002682328","nameIdentifierScheme":"CiNii ID","nameIdentifierURI":"http://ci.nii.ac.jp/nrid/9000002682328"},{"nameIdentifier":"50264809","nameIdentifierScheme":"e-Rad","nameIdentifierURI":"https://kaken.nii.ac.jp/ja/search/?qm=50264809"},{"nameIdentifier":"read0185340","nameIdentifierScheme":"researchmap","nameIdentifierURI":"https://researchmap.jp/read0185340"}]}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"research report","resourceuri":"http://purl.org/coar/resource_type/c_18ws"}]},"item_title":"インテグリンリンクドキナーゼ不活化遺伝子導入による神経原線維変化モデルの開発","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"インテグリンリンクドキナーゼ不活化遺伝子導入による神経原線維変化モデルの開発","subitem_title_language":"ja"}]},"item_type_id":"6","owner":"12","path":["243"],"pubdate":{"attribute_name":"PubDate","attribute_value":"2007-08-30"},"publish_date":"2007-08-30","publish_status":"0","recid":"3016","relation_version_is_last":true,"title":["インテグリンリンクドキナーゼ不活化遺伝子導入による神経原線維変化モデルの開発"],"weko_creator_id":"12","weko_shared_id":-1},"updated":"2024-05-28T02:24:57.034645+00:00"}