Downstream of Akt in the tumor vessel

描述（由申请人提供）：我们发现Akt信号传导有助于肿瘤血管基质中一些更显著的异常。血管异常包括导致组织水肿和血流缓慢的过度血管渗透性的倾向，改变细胞外微环境的纤维蛋白和其他基质蛋白的外渗，以及炎症细胞和肿瘤细胞进出肿瘤相关脉管系统的运输。我们的总体假设是控制慢性渗透性的相同信号通路也控制白细胞外渗和肿瘤细胞外渗。因此，在本申请中，我们在以下3个目标中测试该假设。目的1验证Akt介导的GSK 3失活介导的基线通透性的假设，并探讨Akt到mTOR的信号通路，其有助于血管生成和血管通透性，以及改变内皮细胞和肿瘤细胞中GSK 3磷酸化的信号通路。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运输中的作用。目标3：检验Akt对慢性渗透性、白细胞粘附和渗出以及肿瘤细胞转移的影响是通过Akt失活GSK 3和随后Snail抑制VE-钙粘蛋白介导的假设。疾病相关性：公共卫生相关性：我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，我们还研究了临床上可行的靶向这一途径的方法。本申请旨在探索一些介导内皮Akt信号传导在病理性血管生成（包括癌症）中的作用的下游信号传导途径。虽然Akt通路抑制剂正在开发中，但利用这些抑制剂的大多数癌症研究都集中在抑制肿瘤细胞信号传导上。我们已经发现，在临床前模型中，血管对雷帕霉素的反应是Akt通路抑制剂功效的重要部分。我们对这个项目的希望是，通过仔细检查Akt在病理性血管生成中的功能的介导物，我们可以发现新的基质靶点，以扩大癌症治疗的全部功能。此外，我们希望通过探索该途径的未充分研究的基质效应，显着帮助在癌症中有效使用现有Akt途径抑制剂的进展。我们期望我们的发现不仅与肿瘤进展的管理有关，而且在预防转移方面具有特殊的应用

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