FLK1 SINALING PROTECTS TUMOR VASCULATURE FROM RADIATION

FLK1 Sinaling 保护肿瘤脉管系统免受辐射

• 批准号: 6262545
• 负责人: DENNIS E HALLAHAN
• 金额: $ 25.6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-12 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6262545
• 关键词: Adenoviridae; BCL2 gene /protein; apoptosis; astrocytoma; athymic mouse; biological signal transduction; cell migration; cell proliferation; cysteine endopeptidases; enzyme activity; enzyme inhibitors; fluorescence microscopy; growth factor receptors; inhibitor /antagonist; ionizing radiation; melanoma; neoplasm /cancer blood supply; neoplasm /cancer radiation therapy; phosphatidylinositol 3 kinase; protein kinase; radiation resistance; transfection /expression vector; vascular endothelial growth factors; vascular endothelium; western blottings

DESCRIPTION: (Applicant's Abstract) Tumor blood flow increases after x-irradiation. Similarly, the tumor vascular window model shows that tumor blood vessels are resistant to radiation as compared to blood vessels in more sensitive tumors. The applicant proposes that the signal transduction pathways required for endothelial survival and repair are targets to improve the therapeutic effects of ionizing radiation. The survival pathway activated by angiogenic ligands, such as VEGF and angiopoietein-1, mediate signal transduction through PI3 kinase and protein kinase B (Akt). Akt in turn, inhibits programmed cell death (apoptosis) by increased expression of Bcl-2 and Bcl-XL and through phosphorylation of Bad. His preliminary data show that inhibition of Flk-1 or PI3 kinase blocks the survival pathway and allows for radiation-induced apoptosis. He has focused on the VEGF R2 (Flk-1) receptor tyrosine kinase by use of specific inhibitors of Flk-1 (soluble Flk-1 and SU5416). Flk-1 inhibition enhanced radiation-induced apoptosis and HUVEC and 3B11 endothelial cells. Likewise, inhibitors of PI3 kinase block the survival pathway and enhance radiation-induced apoptosis in endothelial cells. To determine whether Flk-1 inhibition enhances the radiation effect in tumor vascular endothelium, he utilized the tumor vascular window and tumor blood flow analysis by Doppler ultrasound. The applicant's preliminary data show that both soluble Flk-1 and SU5416 block the resistance phenotype in vascular endothelium in blood vessels of all tumor types. Flk-1 also activates an endothelial repair pathway that consists of proliferation, migration and recruitment of endothelial progenitor cells. He, therefore, studied recruitment of endothelial progenitor cells into irradiated tumors. This showed that Flk-1+ endothelial progenitors extravasate from the tumor microvasculature into the perivascular space of irradiated tumors. He hypothesizes that the Flk-1 receptor is required for this repair process and that Flk-1 inhibition will improve radiation responsiveness in tumors. In the proposed studies, the applicant will determine the mechanisms of Flk-1-mediated survival in irradiated tumor blood vessels. He will study signal transduction through PI3 kinase and Akt. He will also determine whether this signal transduction pathway inhibits radiation-induced apoptosis by increased expression of Bcl-2 of Bcl-XL and phosphorylation of Bad. He will determine whether the Flk-1 receptor is required for repair of the tumor microvascular endothelium. Each of these findings will be applied to Specific Aim 4, in which he will optimize the administration of Flk-1 inhibitors to improve the tumor control by ionizing radiation.

描述：（申请人的摘要）肿瘤血流量增加后， X射线照射。类似地，肿瘤血管窗口模型显示， 血管对辐射有抵抗力， 敏感肿瘤申请人提出，信号转导途径 内皮细胞存活和修复所需的是改善 电离辐射的治疗效果。激活的生存途径 血管生成配体如VEGF和血管生成素-1介导信号传导， 通过PI 3激酶和蛋白激酶B（Akt）转导。反过来， 通过增加Bcl-2的表达抑制程序性细胞死亡（凋亡）， Bcl-XL和通过Bad的磷酸化。他的初步数据显示， Flk-1或PI 3激酶的抑制阻断了存活途径， 辐射诱导的细胞凋亡。他专注于VEGF R2（Flk-1）受体 通过使用Flk-1的特异性抑制剂（可溶性Flk-1和 SU5416）。Flk-1抑制增强辐射诱导的凋亡和HUVEC， 3B 11内皮细胞。同样，PI 3激酶抑制剂阻断了 途径并增强辐射诱导的内皮细胞凋亡。到 确定Flk-1抑制是否增强肿瘤中的辐射效应 血管内皮，他利用肿瘤血管窗和肿瘤血 多普勒超声血流分析。申请人的初步数据显示， 可溶性Flk-1和SU 5416都阻断了血管内皮细胞的抗性表型， 所有肿瘤类型的血管内皮。Flk-1还激活了 内皮修复途径包括增殖、迁移和 内皮祖细胞的募集。因此，他研究了招聘 内皮祖细胞移植到受辐射的肿瘤中。这表明Flk-1+ 内皮祖细胞从肿瘤微血管系统外渗到 照射肿瘤的血管周围空间。他假设Flk-1 这种修复过程需要Flk-1受体，Flk-1抑制将 提高肿瘤放射反应性。在拟议的研究中， 申请人将确定Flk-1介导的存活的机制， 照射的肿瘤血管。他将通过PI 3研究信号转导 激酶和Akt。他还将确定这种信号传导途径 通过增加Bcl-XL的Bcl-2表达抑制辐射诱导的细胞凋亡 和Bad的磷酸化。他将确定Flk-1受体是否 这是修复肿瘤微血管内皮所必需的。这一切成功都 研究结果将应用于具体目标4，其中他将优化 施用Flk-1抑制剂以通过电离提高肿瘤控制 辐射