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度导致组织水肿和血流缓慢，纤维蛋白和其他基质蛋白外渗，改变细胞外微环境，炎症细胞和肿瘤细胞进出肿瘤相关的血管系统。我们的总体假设是控制慢性渗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3个目标中测试这一假设。目的1：验证GSK3失活介导Akt驱动的基线通透性的假设，探索内皮细胞和肿瘤细胞中从Akt到mTOR的促进血管生成和血管通透性的信号通路，以及改变GSK3磷酸化的信号通路。目的2：探索Akt和下游信号通路在白细胞和肿瘤细胞跨内皮运输中的作用。目的3：验证Akt对慢性通透性、白细胞粘附、浸润和肿瘤细胞转移的影响是通过Akt对GSK3的失活和随后的VE-cadherin的Snail抑制来介导的。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信号通路，但目前实验室的重点是Akt信号通路，它是如何被调节的，以及它是如何调节微血管形成和功能的。除了探索分子机制外，我们还研究临床可行的方法来靶向这一途径。该应用旨在探索介导内皮Akt信号在病理性血管生成（包括癌症）中的作用的一些下游信号通路。虽然Akt通路抑制剂正在开发中，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传导上。我们发现血管对雷帕霉素的反应是Akt通路抑制剂在临床前模型中发挥作用的重要组成部分。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介质，我们可以发现新的基质靶点，以扩大癌症治疗的范围。此外，我们希望通过探索Akt通路中尚未充分研究的基质效应，在有效利用现有Akt通路抑制剂治疗癌症方面取得重大进展。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