Downstream of Akt in the tumor vessel

肿瘤血管中 Akt 的下游

• 批准号: 8304361
• 负责人: William C Aird
• 金额: $ 45.28万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304361
• 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; 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; response; trafficking; tumor; tumor progression

Summary: 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: 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

概括： 我们发现AKT信号传导有助于肿瘤血管中一些更明显的异常 基质。血管异常包括导致组织过度血管通透性的倾向 水肿和血流缓慢，纤维蛋白和其他改变细胞外的基质蛋白的渗出 微环境以及炎症细胞和肿瘤细胞的运输中和肿瘤相关的 脉管系统。我们的总体假设是控制慢性渗透性的相同信号通路 控制白细胞渗出和肿瘤细胞渗出。因此，在此应用程序中，我们正在测试此 以下3个目标中的假设。 AIM 1检验以下假设：灭活GSK3介导了Akt驱动的基线渗透性和 探索从AKT到MTOR的信号通路，有助于血管生成和血管 渗透性和在内皮细胞和肿瘤细胞中改变GSK3磷酸化的信号 目标2：探索AKT和下游信号通路在细胞运输中的作用 白细胞和肿瘤细胞遍布整个内皮。 目标3：检验Akt对慢性渗透性，白细胞粘附和 通过Akt灭活GSK3和随后的 蜗牛抑制VE-钙黏着蛋白。疾病相关性： 我实验室的总体目标是研究控制血管生成的信号通路的整合 和微血管功能。没有一个项目可以一次研究所有途径，但是实验室的当前重点是 在AKT信号通路上，如何调节其调节微血管形成和功能。在 除了探索分子机制，我们还研究了临床可行的方法 路径。该应用程序提议探索一些介导的下游信号通路 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。而AKT途径抑制剂 正在开发中，大多数利用这些抑制剂的癌症研究都集中在抑制上 肿瘤细胞信号传导。我们发现，对雷帕霉素的血管反应是AKT的重要组成部分 途径抑制剂在临床前模型中的功效。我们对这个项目的希望是，通过仔细检查 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展 癌症治疗术的曲目。此外，我们希望大力帮助有效的进步 通过探索该途径的研究研究的基质效应，在癌症中使用现有的AKT途径抑制剂。 我们预计我们的发现不仅与肿瘤进展的管理有关 预防转移的特殊应用

项目成果

Overexpression of MyrAkt1 in endothelial cells leads to erythropoietin- and BMP4-independent splenic erythropoiesis in mice.

内皮细胞中 MyrAkt1 的过度表达导致小鼠体内不依赖促红细胞生成素和 BMP4 的脾脏红细胞生成。

• DOI: 10.1371/journal.pone.0055095
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: O'Donnell,RebekahK;Goldstein,WhitneyE;Perruzzi,Carole;Benjamin,LauraE;Aird,WilliamC
• 通讯作者: Aird,WilliamC

VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth.

• DOI: 10.1158/0008-5472.can-14-3023
• 发表时间: 2016-02
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Rebekah K. O’Donnell;Beverly L. Falcón;J. Hanson;Whitney E. Goldstein;C. Perruzzi;S. Rafii;W. Aird