γ-secretase抑制剂阻断Notch信号通道抗胶质瘤新生血管的作用分析-外科学(神经外科)专业论文.docxVIP

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γ-secretase抑制剂阻断Notch信号通道抗胶质瘤新生血管的作用分析-外科学(神经外科)专业论文.docx

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γ-secretase抑制剂阻断Notch信号通道抗胶质瘤新生血管的作用分析-外科学(神经外科)专业论文

第二军医大学博士学位论文第二军医大学博士学位论文 γ-secretase γ-secretase 抑制剂阻断 Notch 信号通道抗胶质瘤新生血管的作用研究 - - PAGE 4 - - - PAGE 5 - Abstract BLOCKADE OF NOTCH SIGNALING WITH Γ-SECRETASE INHIBITOR IN GLIOMA ANTIANGIOGENESIS THERAPY Part 1: Expression and significance of Delta-like 4 in glioma Objectives: As one of Notch legands, Delta-like 4 (DLL4) was mainly expressed on endothelial cells. The objective of our research was to study the expression of Delta-like 4 (DLL4), as well as the correlation with microvessel density (MVD) in glioma. Methods: 40 cases of glioma (classⅠ, 12 cases; classⅡ,13 cases; classⅢ~Ⅳ, 15 cases) were immunohistochemistically analyzed with monoclone anti-DLL4 antibody and polyclone anti-CD31 antibody, expression level of DLL4 was measured with Image-Pro Plus 6.0 via optical density analysis. MVD was calculated. Results: OD of class Ⅰ , Ⅱ , Ⅲ ~ Ⅳ were 514.71+179.56, 961.97+88.53, 1125.31+225.35，respectly (p0.01). MVD of classⅠ,Ⅱ,Ⅲ~Ⅳ were 24.75+10.33, 57.62+12.45, 114.60+25.28, respectly (p0.01). Correlation coefficient between MVD and OD of DLL4 was 0.68 (p0.01). Conclusions: The level of DLL4 closely correlates with glioma histological grade and MVD. It is significant to detect the expression level of DLL4 to evaluate the biological behavior and blood supply of glioma. Considering the difficulty of DLL4 inhibition in clinical practice and the specific blockade of γ-secretase inhibitor on DLL4 receptor Notch, we will investigate the effects and mechanisms of γ-secretase inhibitor in glioma antiangiogenic therapy. KEY WORDS: Delta-like 4, glioma, microvessel density, Notch Part 2: Effects of γ-secretase inhibitor on endothelial cells Objective: Previous researches had documented that Notch signaling had important role in angiogenesis and vascular function development. The objective of this study was to investigate the regulation of Vascular Endothelial Growth Factor Receptor (VEGFR) and endothelial cell proliferation by γ-secretase inhibitor. Materials and Methods: 1×