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Development of the Gene Therapy with a CRE Decoy ODN to Prevent Vascular Intimal Hyperplasia
https://asahikawa-med.repo.nii.ac.jp/records/6078
https://asahikawa-med.repo.nii.ac.jp/records/6078bd88b436-4895-4ce1-a0d0-aa3df38bd343
| 名前 / ファイル | ライセンス | アクション |
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7255.pdf (122.4 kB)
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| Item type | 学位論文 / Thesis or Dissertation_02(1) | |||||||||
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| 公開日 | 2019-08-01 | |||||||||
| タイトル | ||||||||||
| タイトル | Development of the Gene Therapy with a CRE Decoy ODN to Prevent Vascular Intimal Hyperplasia | |||||||||
| 言語 | en | |||||||||
| 言語 | ||||||||||
| 言語 | jpn | |||||||||
| キーワード | ||||||||||
| 主題Scheme | Other | |||||||||
| 主題 | CRE | |||||||||
| キーワード | ||||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Decoy | |||||||||
| キーワード | ||||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Gene therapy | |||||||||
| キーワード | ||||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Intimal hyperplasia | |||||||||
| 資源タイプ | ||||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_46ec | |||||||||
| 資源タイプ | thesis | |||||||||
| 著者 |
内田, 大貴
× 内田, 大貴
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| 著者 ローマ字 | ||||||||||
| Uchida, Daiki | ||||||||||
| 書誌情報 |
Journal of vascular surgery 発行日 2019-06-01 |
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| ISSN | ||||||||||
| 収録物識別子タイプ | ISSN | |||||||||
| 収録物識別子 | 0741-5214 | |||||||||
| DOI | ||||||||||
| 識別子タイプ | DOI | |||||||||
| 関連識別子 | 10.1016/j.jvs.2019.02.042 | |||||||||
| 識別番号 その他 | ||||||||||
| 内容記述タイプ | Other | |||||||||
| 内容記述 | PMID：31204215 | |||||||||
| 学位授与番号 | ||||||||||
| 学位授与番号 | 10107A534 | |||||||||
| 学位名 | ||||||||||
| 学位名 | 博士（医学） | |||||||||
| 学位授与機関 | ||||||||||
| 学位授与機関名 | 旭川医科大学 | |||||||||
| 抄録 | ||||||||||
| 内容記述タイプ | Abstract | |||||||||
| 内容記述 | OBJECTIVE: \nIntimal hyperplasia (IH) is the main cause of therapeutic failure after vascular and endovascular surgery. However, there is currently no targeted therapy for the treatment of IH. We recently reported that the inhibition of cyclic adenosine monophosphate response element (CRE) binding protein (CREB) activation is important in vein graft IH. We focused on a decoy oligodeoxynucleotide (ODN) therapeutic strategy for suppressing IH as a clinical application. The objective of this study was to confirm the therapeutic effect of a CRE decoy ODN in an animal model as a novel therapy for preventing intimal hyperplasia as the first step of the preclinical study of our strategy. METHODS: \nWe designed two phosphorothioate CREs and two scramble decoy ODNs and screened them using a CREB transcription assay to check their ability to bind to a CRE sequence. We chose a CRE decoy ODN with high first-binding ability and transfected it into vascular smooth muscle cells (VSMCs) in vitro. Proliferation and migration were assessed using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays and modified Boyden chamber assays. We examined CRE activity using a luciferase reporter gene assay. We assessed the expression of messenger RNAs by quantitative real-time polymerase chain reaction. In a wire-injury mouse model (C57BL6, n = 6), CRE decoy ODN was transfected into the injured vessel wall using an ultrasound-sonoporation method in vivo. Mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3) and four and a half LIM domains 5 (FHL5) expression of pregrafting vein remnants were assessed by immunohistologic analyses. RESULTS: \nCompared with scramble decoy ODN, the selected CRE decoy ODN could significantly decrease CRE activity (mean ± standard error of the mean: 0.20 ± 0.03 vs 1.00 ± 0.16, n = 6; P < .05) as shown by a luciferase reporter gene assay, VSMC proliferation (0.73 ± 0.04 vs 0.89 ± 0.02, n = 6; P < .05) and migration (96.4 ± 6.1 vs 311.4 ± 19.1 migrated VSMCs/well, n = 6; P < .05) after 24-hour transfection. The CRE decoy ODN significantly suppressed the formation of IH at injured vessel walls in an animal model, as analyzed by pathologic staining (0.20 ± 0.02 vs 0.56 ± 0.08, area of the intima/area of the artery vs the control after 21 days' transfection, n = 6; P < .05). Furthermore, MAPKAPK3 and FHL5, which are CREB activators, were significantly expressed in pregrafting vein remnants in diabetes mellitus patients. CONCLUSIONS: \nCREB-CRE signaling is an important mechanism of IH formation, and CRE decoy therapy can help preventing IH. This study is the first part of the preclinical study of our strategy. |
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| 内容記述タイプ | Other | |||||||||
| 内容記述 | application/pdf | |||||||||
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| 内容記述タイプ | Other | |||||||||
| 内容記述 | application/pdf | |||||||||
