{"created":"2023-07-26T01:11:41.884031+00:00","id":2001057,"links":{},"metadata":{"_buckets":{"deposit":"e33cad8b-a154-4c24-a540-335ae7018353"},"_deposit":{"created_by":4,"id":"2001057","owners":[4],"pid":{"revision_id":0,"type":"depid","value":"2001057"},"status":"published"},"_oai":{"id":"oai:niigata-u.repo.nii.ac.jp:02001057","sets":["453:455","471:561:562"]},"author_link":[],"item_6_date_granted_51":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"2023-03-23"}]},"item_6_degree_grantor_49":{"attribute_name":"学位授与機関","attribute_value_mlt":[{"subitem_degreegrantor":[{"subitem_degreegrantor_language":"ja","subitem_degreegrantor_name":"新潟大学"},{"subitem_degreegrantor_language":"en","subitem_degreegrantor_name":"Niigata University"}],"subitem_degreegrantor_identifier":[{"subitem_degreegrantor_identifier_name":"13101","subitem_degreegrantor_identifier_scheme":"kakenhi"}]}]},"item_6_degree_name_48":{"attribute_name":"学位名","attribute_value_mlt":[{"subitem_degreename":"博士(医学)","subitem_degreename_language":"ja"}]},"item_6_description_4":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"近年,脳梗塞患者の機能回復を促進する方法として,細胞療法が注目されている.当研究室では,低酸素低糖刺激(OGD)を加えたラット末梢血単核球(OGD-PBMC)が組織保護的な極性に変化し,脳梗塞ラットに経頸動脈投与することで脳内の血管内皮増殖因子(VEGF)増加を介して脳梗塞治療効果を有することを示した.一方で,低酸素条件下では,低酸素誘導因子(HIF-1α)の増加によりVEGFが増加することも報告されているが,OGD刺激を加えたPBMCで同様の機序が働いているかは検証されていなかった.また,PBMCと脳内常在細胞との細胞間相互作用の機序は明確ではなかった.そこで,OGD-PBMCの脳梗塞に対する治療効果の機序について,細胞間相互作用にエクソソームが関与していると想定し,HIF-1α発現とVEGF分泌に関わるmiRNAに注目して検討した.ヒトOGD-PBMCを一過性局所脳梗塞モデルラットに経頸動脈投与して,脳内への生着を検証した.さらに,ミクログリアに対する極性変化の誘導の有無を,抗VEGF抗体を用いて蛍光免疫染色で検証した.次に,通常培養したPBMC(Normoxic-PBMC),OGD-PBMCそれぞれのエクソソーム由来の200bp以下のRNAを濃縮し,HIF-1αの発現に関与するmiRNAを比較した.その結果を踏まえ,HIF-1αとVEGFを増加させる可能性のあるmiRNAに対するアンチセンスオリゴヌクレオチド投与による阻害を行い,Normoxic-PBMCとOGD-PBMCにおけるHIF-1αとVFGFの発現をウエスタンブロッティングとルミネックスアッセイで評価した.ヒトOGD-PBMCは,投与3日後には梗塞部位周囲で確認されたが,投与21日後には確認されなかった.一方,VEGFを発現しているミクログリアはNormoxic-PBMC投与群に比して,OGD-PBMC投与群で3.9倍に増加した(P<0.05).HIF-1αまたはVEGFの発現増加に関わるmiRNAの中で,唯一miR-155-5pがNormoxic-PBMCと比して,OGD-PBMCでは0.37倍にダウンレギュレートしていた(P=0.01).miR-155-5p阻害を行ったヒトOGD-PBMCでは,HIF-1αの発現が3倍に増加した(P<0.05).また,VEGFの発現も1.36倍に増加した(P<0.05).一方,Normoxic-PBMCではmiR-155-5p阻害にてHIF-1αの発現は検出されなかった.以上から,OGD-PBMCでは,miR-155-5pの減少によりHIF-1αの発現が増加しVEGFの分泌が増加する.さらに,OGD-PBMC投与による組織保護的極性の獲得にはエクソソームを介した細胞間情報伝達が関与している可能性が示唆された.","subitem_description_language":"ja","subitem_description_type":"Abstract"}]},"item_6_description_53":{"attribute_name":"学位記番号","attribute_value_mlt":[{"subitem_description":"新大院博(医)第1110号","subitem_description_language":"ja","subitem_description_type":"Other"}]},"item_6_dissertation_number_52":{"attribute_name":"学位授与番号","attribute_value_mlt":[{"subitem_dissertationnumber":"甲第5119号"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"open access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_abf2"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"大津, 裕","creatorNameLang":"ja"},{"creatorName":"Otsu, Yutaka","creatorNameLang":"en"}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_access","date":[{"dateType":"Available","dateValue":"2023-07-26"}],"displaytype":"detail","filename":"r4nmk1110.pdf","filesize":[{"value":"916KB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"本文","objectType":"fulltext","url":"https://niigata-u.repo.nii.ac.jp/record/2001057/files/r4nmk1110.pdf"},"version_id":"2b495408-7733-4de8-b120-ccae1e94b2a4"},{"accessrole":"open_access","date":[{"dateType":"Available","dateValue":"2023-07-26"}],"displaytype":"detail","filename":"r4nmk1110_a.pdf","filesize":[{"value":"528KB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"要旨","objectType":"abstract","url":"https://niigata-u.repo.nii.ac.jp/record/2001057/files/r4nmk1110_a.pdf"},"version_id":"5246a9ec-ce03-46b7-b645-f56e90fdf504"}]},"item_keyword":{"attribute_name":"キーワード","attribute_value_mlt":[{"subitem_subject":"脳梗塞","subitem_subject_language":"ja","subitem_subject_scheme":"Other"},{"subitem_subject":"細胞療法","subitem_subject_language":"ja","subitem_subject_scheme":"Other"},{"subitem_subject":"末梢血単核球","subitem_subject_language":"ja","subitem_subject_scheme":"Other"},{"subitem_subject":"低酸素低糖刺激","subitem_subject_language":"ja","subitem_subject_scheme":"Other"},{"subitem_subject":"miR-155-5p","subitem_subject_language":"en","subitem_subject_scheme":"Other"},{"subitem_subject":"HIF-1α","subitem_subject_language":"en","subitem_subject_scheme":"Other"},{"subitem_subject":"VEGF","subitem_subject_language":"en","subitem_subject_scheme":"Other"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"doctoral 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