Downstream of Akt in the tumor vessel

肿瘤血管中 Akt 的下游

• 批准号: 7825452
• 负责人: LAURA E BENJAMIN
• 金额: $ 46.92万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825452
• 关键词: Acute; Adherence; Adhesions; Blood Vessels; Blood flow; Cadherins; Categories; Cells; Chronic; Data; Development; Disease; Edema; Endothelial Cells; Endothelium; Event; Extravasation; Fibrin; Genetic Transcription; Goals; Infiltration; Inflammatory; Investigation; Laboratories; Left; Leukocyte Trafficking; Leukocytes; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Molecular; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Pathologic Neovascularization; Pathway interactions; Permeability; Phosphorylation; Play; Pre-Clinical Model; Proteins; Repression; Role; Signal Pathway; Signal Transduction; Sirolimus; Snails; Stimulus; Testing; Therapeutic; TimeLine; Tissues; Tumor-Associated Vasculature; Vascular Permeabilities; Work; angiogenesis; cadherin 5; extracellular; human FRAP1 protein; in vitro Model; inhibitor/antagonist; macrophage; neoplastic cell; novel; pre-rapamycin; prevent; public health relevance; response; trafficking; tumor; tumor progression

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

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明显的异常。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，纤维蛋白的渗出和其他改变细胞外微环境的基质蛋白，以及炎症细胞和肿瘤细胞在肿瘤相关的血管中的运输。我们的总体假设是控制慢性渗透性的相同信号通路，还控制着白细胞渗出和肿瘤细胞渗出。因此，在此应用程序中，我们在以下3个目标中检验了这一假设。 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白细胞和肿瘤细胞遍布整个内皮。 AIM 3：检验Akt对慢性渗透性，白细胞粘附和尿布的影响的假设以及肿瘤细胞转移是通过Akt灭活GSK3以及随后对VE-钙粘着蛋白的蜗牛抑制来介导的。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。没有一个项目可以一次研究所有途径，但是实验室的当前焦点是在AKT信号通路上，如何调节它以及如何调节微血管形成和功能。除了探索分子机制外，我们还研究了临床上可行的方法以靶向这一途径。该应用程序提议探索一些下游信号通路，以介导内皮AKT信号传导在包括癌症在内的病理血管生成中的影响。尽管正在开发AKT途径抑制剂，但使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。我们发现，对雷帕霉素的血管反应是AKT途径抑制剂在临床前模型中的功效的重要组成部分。我们对该项目的希望是，通过仔细研究AKT在病理血管生成中功能的介体，我们可以发现新颖的基质靶标，以扩大癌症治疗剂的曲目。此外，我们希望通过探索该途径的研究不足的基质效应来有效地帮助有效利用现有的AKT途径抑制剂的进步。我们预计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