本資料は、掲載誌(URI)等のリンク先にある学位授与機関のWebサイトやCiNii Dissertationsから、本文を自由に閲覧できる場合があります。
博士論文
国立国会図書館館内限定公開
収録元データベースで確認する
国立国会図書館デジタルコレクション
デジタルデータあり
公開元のウェブサイトで確認する
DOI[10.14943/doctoral.k11282]のデータに遷移します
固形腫瘍の再酸素化における一酸化窒素の役割とその生成機構
- 国立国会図書館永続的識別子
- info:ndljp/pid/8953171
国立国会図書館での利用に関する注記
資料に関する注記
一般注記:
- Low oxygen conditions drastically decreases cellular radiosensitivity and facilitate the adaptive responses of tumor. Hence, hypoxic regions in solid ...
書店で探す
障害者向け資料で読む
全国の図書館の所蔵
国立国会図書館以外の全国の図書館の所蔵状況を表示します。
所蔵のある図書館から取寄せることが可能かなど、資料の利用方法は、ご自身が利用されるお近くの図書館へご相談ください
書店で探す
障害者向け資料で読む
書誌情報
この資料の詳細や典拠(同じ主題の資料を指すキーワード、著者名)等を確認できます。
デジタル
- 資料種別
- 博士論文
- 著者・編者
- 永根, 大幹
- 著者標目
- 出版年月日等
- 2014-03-25
- 出版年(W3CDTF)
- 2014-03-25
- 並列タイトル等
- The mechanism of radiation-induced endothelial nitric oxide synthase activation and its role in tumor reoxygenation after X-irradiation
- 寄与者
- 稲波, 修木村, 和弘高木, 哲山盛, 徹
- 授与機関名
- 北海道大学
- 授与年月日
- 2014-03-25
- 授与年月日(W3CDTF)
- 2014-03-25
- 報告番号
- 甲第11282号
- 学位
- 博士(獣医学)
- 博論授与番号
- 甲第11282号
- 本文の言語コード
- jpneng
- 著者別名
- NDC
- 対象利用者
- 一般
- 一般注記
- Low oxygen conditions drastically decreases cellular radiosensitivity and facilitate the adaptive responses of tumor. Hence, hypoxic regions in solid tumor are well-known obstacle for successful radiotherapy. It occurs mainly as a result of the excess proliferation of tumor cells and accompanying deficiency in blood and nutrient supplies. It has been reported that ionizing radiation (IR) decreases hypoxic regions in tumor, leading to the improvement of radiosensitivity of solid tumor. However, the mechanism of IR-induced tumor reoxygenation has not been elucidated. In the first study, to clarify the effect of radiation-induced nitric oxide (NO) on tumor oxygenation status and the NOS isoforms responsible for the NO production after IR, transplanted SCCVII tumor was employed. Tumor oxygenation status after IR was evaluated by in vivo electron spin resonance method with the oxygen sensitive probe, immunohistochemical technique with two different hypoxia probes, and Hoechst33342 perfusion assay. It was shown that IR increased tissue pO2 and tissue perfusion after IR. In addition, decrease of the hypoxic regions in tumor was observed after IR. To clarify the involvement of NO in this reoxygenation, a wide-range NOS inhibitor L-NAME was administered to tumor-bearing mice. L-NAME treatment significantly attenuated reoxygenation in hypoxic regions after IR. These results suggested that IR increased NO production that increased tissue perfusion in tumor, leading to the tumor reoxygenation. In mammalian cells, there are three NOS isoforms, endothelial NOS (eNOS), inducible NOS (iNOS), and neural NOS (nNOS). To determine the NOS isoforms responsoble for NO-induced reoxygenation, RT-qPCR analysis, Western blot analysis, and NOS activity assay were used. RT-qPCR analysis showed that nNOS hardly expressed in SCCVII tumor, and that IR did not increase mRNA of NOS isoforms. Western blot analysis showed IR did not increase protein expression of iNOS and eNOS. NOS activity assay revealed that IR increased NOS activity, and iNOS was not involved in this activity. In addition, immunohistochemistry showed that eNOS was expressed in vascular endothelial cells of tumor. These results suggested that IR increased eNOS activity in vascular endothelial cells, leading to the tumor reoxygenation. However, the mechanism of eNOS activation after IR remains unclear. In the second study, bovine aortic endothelial cells (BAEC) were employed to investigate the mechanisms eNOS activation in vitro after IR. As a mechanism of eNOS activation, phosphorylation of eNOS-Ser1179 by Ser/Thr kinases is a critical step. IR is known to induce DNA-double strand breaks (DSBs) and elicit subsequent various adaptive responses toward IR. Ataxia telangiectasia mutated (ATM) plays an important role in coordinating the cellular response to DSBs. In addition to kinases, HSP90 has also been identified as an important regulator modifying ATM function after IR. In this study, I aimed to clarify the involvement of DNA-damage response in IR-induced eNOS activation. NOS activity assay showed that IR increased NOS activity at 12 and 24 h after IR. In these time points, eNOS-Ser1179 phosphorylation was increased. ATM phosphorylation was increased at 0.5 h after IR, and lasted to 24 h. An ATM inhibitor Ku-60019 inhibited eNOS and ATM phosphorylation after IR. NOS activity was attenuated by Ku-60019. Similarly, a HSP90 inhibitor geldanamycin inhibited ATM and eNOS phosphorylation, and eNOS activation. These results suggested that IR increased eNOS activity through HSP90/ATM pathway. In conclusion, this study provides new insight for mechanisms in radiation-induced tumor reoxygenation. IR increases eNOS activity via DNA damage response. Activation of eNOS increases tissue perfusion through the production of NO and reoxygenates the hypoxic regions in solid tumor. This radiation-induced tumor reoxygenation increases tumor radiosensitivity toward subsequent irradiation, providing the new insight for the improvement of radiotherapy by modulating eNOS activity.(主査) 教授 稲波 修, 教授 木村 和弘, 准教授 高木 哲, 准教授 山盛 徹獣医学研究科(獣医学専攻)
- DOI
- 10.14943/doctoral.k11282
- 国立国会図書館永続的識別子
- info:ndljp/pid/8953171
- コレクション(共通)
- コレクション(障害者向け資料:レベル1)
- コレクション(個別)
- 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
- 収集根拠
- 博士論文(自動収集)
- 公開開始日(W3CDTF)
- 2015-03-03
- 受理日(W3CDTF)
- 2015-02-03T05:25:05+09:00
- 作成日(W3CDTF)
- 2014
- 記録形式(IMT)
- PDF
- オンライン閲覧公開範囲
- 国立国会図書館内限定公開
- デジタル化資料送信
- 図書館・個人送信対象外
- 遠隔複写可否(NDL)
- 可
- 連携機関・データベース
- 国立国会図書館 : 国立国会図書館デジタルコレクション