Molecular Dissection of the Angiogenic Response induced by VEGF-A

我们发现Akt信号与肿瘤血管中一些更显著的异常有关 伊特罗玛。这些血管异常包括血管通透性过高的倾向导致 组织水肿和血流迟缓，纤维蛋白和其他基质蛋白渗出，从而改变 细胞外微环境与炎性细胞进出肿瘤相关 脉管系统。此外，我们还发现雷帕霉素是肿瘤中Akt信号的有效抑制剂。 斯特尔玛。这项拨款申请有两个主要目标：(1)研究雷帕霉素对肿瘤间质的影响和 目的：探讨雷帕霉素抗间质作用对其抗肿瘤作用的影响。无论是血管和 将对非血管间质进行研究。(2)探讨关键分子在血管生成中的作用。 Akt-mTOR通路可能对雷帕霉素的疗效观察至关重要。目标1专注于 雷帕霉素血管靶标的鉴定。目的2旨在探讨雷帕霉素对大鼠心脏功能的影响。 非血管肿瘤基质AIM 3研究雷帕霉素抑制肿瘤细胞的跨膜转运 血管内皮细胞与肿瘤转移除了检查雷帕霉素的效果外，这三个目标都包含一些 Akt-mTOR途径中单个分子的研究。提出了一个特别的重点来检查Akt 血管生成和内皮运输调控中的异构体和TORCH反馈给Akt 为了更好地了解雷帕霉素影响的关键调控分子，以介导 观察到的抗基质表型。

We have found that Akt signaling contributes to some of the more notable abnormalities in tumor vascular itroma. Those vascular abnormalities include the propensity for excessive vascular permeability leading to tissue edema and sluggish blood flow, extravasation of fibrin and other matrix proteins that alter the extracellular microenvironment, and the trafficking of inflammatory cells in and out of the tumor-associated vasculature. In addition, we also showed that rapamycin is an effective inhibitor of Akt signaling in the tumor stroma. This grant application has two major goals: (1) to study rapamycin's effects on the tumor stroma and to determine the i.npact of the anti-stromal effects of rapamycin on its anti-tumor efficacy. Both vascular and nonvascular stroma will be studied. (2) to investigate the contribution to angiogenesis by key molecules in the Akt-mTOR pathway that may be critical for the observation effects of rapamycin. Aim 1 is focused on dentification of the vessel targets of rapamycin. Aim 2 is designed to explore the effects of rapamycin on the non-vascular tumor stroma Aim 3 investigates rapamycin inhibition of tumor cell trafficking across the endothelium in metastasis. In addition to examing rapamycin's effects, all three aims contain some investigations of individual molecules in the Akt-mTor pathway. A particular focus is proposed to examine Akt isoforms and the TORCH feedback to Akt in the regulation of angiogenesis and endothelial trafficking in order to better understand the key regulatory molecules that are affected by rapamycin to mediate the observed anti-stromal phenotypes.