金属富勒醇Gd@C82(OH)22调控血管内皮生长因子受体（VEGFR）跨膜信号转导的机制研究

项目名称： 金属富勒醇Gd@C82(OH)22调控血管内皮生长因子受体（VEGFR）跨膜信号转导的机制研究

项目编号： No.21301176

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 李金霞

作者单位： 中国科学院高能物理研究所

项目金额： 25万元

中文摘要： Gd@C82(OH)22纳米颗粒被证实能通过调控肿瘤微环境高效抑制肿瘤的生长与转移。前期研究发现它能显著抑制肿瘤组织新生血管的形成，但其分子机制有待深入研究。本研究拟从Gd@C82(OH)22的结构特点入手，研究它与VEGF和VEGFR的相互作用及其对VEGFR介导的跨膜信号转导的影响。拟用紫外可见吸收光谱和荧光光谱测定Gd@C82(OH)22与VEGF、VEGFR的结合常数及结合个数，用同步辐射圆二色谱和小角散射技术检测Gd@C82(OH)22对VEGF、VEGFR的分子构象及结合的影响，最后用分子动力学模拟技术研究Gd@C82(OH)22与VEGF,VEGFR的结合过程和结合位点，确定Gd@C82(OH)22调控VEGFR介导的跨膜信号转导的方式，初步探索Gd@C82(OH)22的结构及性质与其抗肿瘤效应之间的关系，这对促进其他类似的具有潜在治疗作用的纳米颗粒在医学上的应用具有重要意义

中文关键词： 纳米药物；金属富勒醇；铁摄入；转铁蛋白；肿瘤治疗

英文摘要： Metallofullerene Gd@C82 (OH)22 nanoparticles have been demonstrated to successfully inhibit the tumor growth and metastasis via modulating tumor microenvironment. In our preliminary studies, Gd@C82 (OH)22 nanoparticles exhibited an obvious anti-angiogenesis potency. However, the molecular mechanism underlying the anti-angiogenesis induced by Gd@C82 (OH)22 nanoparticles has not been fully elucidated yet. In the present study, based on the structural characteristics and the physicochemical property of Gd@C82 (OH)22 nanoparticles , we will explore the interaction between Gd@C82 (OH)22 nanoparticles and vascular endothelial growth factor(VEGF) and its receptor VEGFR and the subsequent impact on VEGFR-mediated transmembrane signaling pathways by a combinatorial application of physical, chemical and biological methods. The binding sites number and the apparent binding constant of Gd@C82 (OH)22 nanoparticles and VEGF, VEGFR will be measured by UV-Vis absorption and fluorescence spectroscopy. Furthermore, the conformation change of VEGF, VEGFR upon the binding of Gd@C82 (OH)22 nanoparticles as well as the intervention of the VEGF-VEGFR binding by the nanoparticles will be detected by small angle X-ray scattering(SAXS) and synchrotron radiation circular dichroism (SRCD). Finally, molecular dynamics simulations will be us

英文关键词： nanomedicine；metallofullerenol；iron uptake；transferrin；cancer therapy