FLK1 SINALING PROTECTS TUMOR VASCULATURE FROM RADIATION

描述：(申请人摘要)术后肿瘤血流量增加 X射线照射。同样，肿瘤血管窗模型显示肿瘤 血管对辐射的抵抗力比更多的血管强 敏感的肿瘤。申请人提出，信号转导通路 内皮细胞存活和修复所需的是改善 电离辐射的治疗效果。被激活的生存途径 血管生成配体，如血管内皮生长因子和血管生成素-1，介导信号 通过PI3激酶和蛋白激酶B(Akt)进行信号转导。AKT依次， 通过增加Bcl2和Bcl2的表达来抑制细胞程序性死亡(凋亡) Bc1-xl和Bad的磷酸化。他的初步数据显示， 抑制Flk-1或PI3激酶阻断生存途径并允许 辐射诱导的细胞凋亡。他一直专注于血管内皮生长因子R2(Flk-1)受体 利用Flk-1(可溶性Flk-1和Flk-1)的特异性抑制剂 SU5416)。Flk-1抑制增强辐射诱导的细胞凋亡和HUVEC 3B11内皮细胞。同样，PI3激酶的抑制剂可以阻止存活。 辐射诱导内皮细胞凋亡的途径和增强。至 确定抑制Flk-1是否增强肿瘤的放射效应 血管内皮细胞，他利用肿瘤血管窗和肿瘤血液 用多普勒超声进行血流分析。申请人的初步数据显示， 可溶性Flk-1和SU5416均阻断血管内皮细胞耐药表型 所有肿瘤类型的血管内皮细胞。Flk-1还激活了一个 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 将内皮祖细胞转化为受辐射的肿瘤。这表明Flk-1 内皮祖细胞从肿瘤微血管外溢到血管内皮细胞 受照射肿瘤的血管周围间隙。他假设FLK-1 这种修复过程需要受体，而抑制Flk-1将 提高肿瘤的放射反应能力。在建议的研究中， 申请者将确定Flk-1介导的存活机制 受辐射的肿瘤血管。他将通过PI3研究信号转导 KK和Akt.他还将确定这一信号转导途径是否 上调Bclxl基因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 修复肿瘤微血管内皮细胞所必需的。这其中的每一个 调查结果将应用于具体目标4，在该目标中，他将优化 应用Flk-1抑制剂通过电离提高肿瘤控制 辐射。

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.