Downstream of Akt in the tumor vessel

肿瘤血管中 Akt 的下游

基本信息

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
项目类别：
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

项目摘要

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 信号传导导致肿瘤血管中一些更显着的异常基质。血管异常包括血管通透性过高导致组织水肿和血流缓慢、纤维蛋白和其他改变细胞外基质蛋白的外渗微环境，以及炎症细胞和肿瘤细胞进出肿瘤相关细胞的运输脉管系统。我们的总体假设是控制慢性渗透性的信号通路相同控制白细胞外渗和肿瘤细胞外渗。因此，在这个应用程序中，我们正在测试这个假设有以下3个目标。目标 1 检验 GSK3 失活介导 Akt 驱动的基线通透性的假设探索从 Akt 到 mTOR 的信号通路，有助于血管生成和血管生成通透性以及改变内皮细胞和肿瘤细胞中 GSK3 磷酸化的信号传导目标 2：探讨 Akt 和下游信号通路对细胞运输的作用穿过内皮的白细胞和肿瘤细胞。目标 3：检验 Akt 对慢性通透性、白细胞粘附和慢性通透性影响的假设血细胞渗出和肿瘤细胞转移是通过 Akt 失活 GSK3 介导的 VE-钙粘蛋白的蜗牛抑制。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。没有一个项目可以同时研究所有路径，但实验室当前的重点是关于 Akt 信号通路、它如何被调节以及它如何调节微血管的形成和功能。在除了探索分子机制外，我们还研究临床上可行的方法来针对这一点途径。该申请提议探索一些介导的下游信号通路内皮 Akt 信号传导对病理性血管生成（包括癌症）的影响。而 Akt 通路抑制剂正在开发中，大多数利用这些抑制剂的癌症研究都集中在抑制肿瘤细胞信号传导。我们发现血管对雷帕霉素的反应是 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，通过仔细审查 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来扩展癌症治疗的全部内容。此外，我们希望能够大力帮助实现有效的通过探索该途径尚未充分研究的基质效应，将现有的 Akt 途径抑制剂用于癌症治疗。我们预计我们的发现不仅与肿瘤进展的管理相关，而且与在预防转移方面的特殊应用

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
Rebekah K. O’Donnell;Beverly L. Falcón;J. Hanson;Whitney E. Goldstein;C. Perruzzi;S. Rafii;W. Aird