Downstream of Akt in the tumor vessel

描述(由申请人提供)：我们发现Akt信号与肿瘤血管间质中一些更显著的异常有关。血管异常包括血管通透性过高导致组织水肿和血流迟缓，纤维蛋白和其他基质蛋白渗出改变细胞外微环境，以及炎细胞和肿瘤细胞进出肿瘤相关血管系统。我们的总体假设是，控制慢性通透性的信号通路也控制白细胞外渗和肿瘤细胞外渗。因此，在本应用程序中，我们将在以下三个目标中测试这一假设。目的1验证失活的GSK3介导Akt诱导的基线通透性的假说，探讨Akt至mTor促进血管生成和血管通透性的信号通路以及改变内皮细胞和肿瘤细胞GSK3磷酸化的信号。目的2：探讨Akt及其下游信号通路在白细胞和肿瘤细胞跨内皮细胞转运中的作用。目的：验证Akt对慢性通透性、白细胞黏附、滞留和肿瘤细胞转移的影响是通过Akt失活GSK3和随后蜗牛抑制VE-cadherin来实现的。疾病相关性：公共卫生相关性：我的实验室的总体目标是研究控制血管生成和微血管功能的信号通路的整合。没有一个项目可以同时研究所有的通路，但该实验室目前的重点是Akt信号通路，它是如何调节的，以及它如何调节微血管的形成和功能。除了探索分子机制外，我们还研究了针对这一途径的临床可行方法。这项应用建议探索一些下游信号通路，这些信号通路介导内皮细胞Akt信号在包括癌症在内的病理性血管生成中的作用。虽然Akt途径抑制剂正在开发中，但大多数利用这些抑制剂的癌症研究都集中在抑制肿瘤细胞信号转导上。我们发现，在临床前模型中，对雷帕霉素的血管反应是Akt途径抑制剂疗效的重要组成部分。我们对这个项目的希望是，通过仔细研究Akt在病理性血管生成中的中介作用，我们可以发现新的间质靶点，以扩大癌症治疗的范围。此外，我们希望通过探索未被充分研究的Akt途径的间质效应，为有效利用现有Akt途径抑制剂治疗癌症的进展提供重要的帮助。我们期望我们的发现不仅与肿瘤进展的管理相关，而且在预防转移方面有特殊的应用。

DESCRIPTION (provided by applicant): We have found that Akt signaling contributes to some of the more notable abnormalities in tumor vascular stroma. 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 and tumor cells in and out of the tumor-associated vasculature. Our overall hypothesis is the same signaling pathways that govern chronic permeability also govern leukocyte extravasation and tumor cell extravasation. Thus in this application we are testing this hypothesis in the following 3 aims. Aim 1 Test the hypothesis that inactivation GSK3 mediates Akt-driven baseline permeability and explores the signaling pathway from Akt to mTOR that contributes to angiogenesis and vascular permeability and the signaling that alters GSK3 phosphorylation in endothelial cell and tumor cells Aim 2: To explore the role of Akt and downstream signaling pathways on cellular trafficking of leukocytes and tumor cells across the endothelium. Aim 3: Test the hypothesis that Akt effects on chronic permeability, leukocyte adhesion and diapedesis and tumor cell metastasis are mediated through Akt inactivation of GSK3 and subsequent Snail repression of VE-cadherin. Disease Relevance: PUBLIC HEALTH RELEVANCE: The overall goal of my laboratory is to study the integration of signaling pathways that control angiogenesis and microvascular function. No one project can study all pathways at once, but the current focus of the lab is on the Akt signaling pathway, how it is regulated and how it regulates microvascular formation and function. In addition to exploring molecular mechanisms, we also study clinically feasible approaches to target this pathway. This application is proposing to explore some of the downstream signaling pathways that mediate the effects of endothelial Akt signaling in pathological angiogenesis, including cancer. While Akt pathway inhibitors are under development, most of the cancer studies that utilize those inhibitors are focused on the inhibition of tumor cell signaling. We have found that the vascular response to rapamycin is an important part of that Akt pathway inhibitor's efficacy in preclinical models. Our hope for this project is that by carefully examining the mediators of Akt's function in pathological angiogenesis we can uncover novel stromal targets to expand the repertoire of cancer therapeutics. In addition, we hope to significantly aid in the progress towards an effective use of existing Akt pathway inhibitors in cancer by exploring the understudied stromal effects of this pathway. We anticipate our findings to be relevant not only to the management of tumor progression but to have particular applications in preventing metastasis