Molecular Dissection of the Angiogenic Response induced by VEGF-A

VEGF-A 诱导的血管生成反应的分子剖析

基本信息

批准号：
8459035
负责人：
HAROLD FISHER DVORAK
金额：
$ 28.41万
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：
2002
资助国家：
美国
起止时间：
2002-06-13 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459035
关键词：
Ablation Affect Angiogenesis Inhibitors Applications Grants Avastin Blood Blood Vessels Blood flow Bone Marrow Breast Cancer Model Cells Clinical Clinical Trials Coagulation Process Collaborations Communities Critical Pathways Data Deposition Dermal Dissection Edema Endothelium Estrogens Extravasation Feedback Fibrin Fibrinogen Fibroblasts Future Generations Genes Goals In Vitro Individual Inflammatory Investigation Laboratories Lymphangiogenesis Lymphatic Malignant Neoplasms Mammary gland Mediating Molecular Mothers Neoplasm Metastasis Pathway interactions Pharmacologic Substance Phenotype Plasma Play Primary Neoplasm Protein Isoforms Proteins Regulation Relative (related person)Role Route Signal Pathway Signal Transduction Sirolimus Stromal Cells Stromal Neoplasm System Testing Therapeutic Tissues Tumor-Associated Vasculature Vascular Endothelial Growth Factors Vascular Endothelium Vascular Permeabilities angiogenesis bevacizumab cancer therapy cellular targeting chemotherapy design extracellular human FRAP1 protein in vivo inhibitor/antagonist mTOR Inhibitor mTOR Signaling Pathway malignant breast neoplasm mouse model neoplastic cell novel protein activation response small molecule trafficking tumor vascular bed

项目摘要

We have found that Akt signaling contributes to some of the more notable abnormalities in tumor vascular itroma. Those 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 in and out of the tumor-associated vasculature. In addition, we also showed that rapamycin is an effective inhibitor of Akt signaling in the tumor stroma. This grant application has two major goals: (1) to study rapamycin's effects on the tumor stroma and to determine the i.npact of the anti-stromal effects of rapamycin on its anti-tumor efficacy. Both vascular and nonvascular stroma will be studied. (2) to investigate the contribution to angiogenesis by key molecules in the Akt-mTOR pathway that may be critical for the observation effects of rapamycin. Aim 1 is focused on dentification of the vessel targets of rapamycin. Aim 2 is designed to explore the effects of rapamycin on the non-vascular tumor stroma Aim 3 investigates rapamycin inhibition of tumor cell trafficking across the endothelium in metastasis. In addition to examing rapamycin's effects, all three aims contain some investigations of individual molecules in the Akt-mTor pathway. A particular focus is proposed to examine Akt isoforms and the TORCH feedback to Akt in the regulation of angiogenesis and endothelial trafficking in order to better understand the key regulatory molecules that are affected by rapamycin to mediate the observed anti-stromal phenotypes.

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 ITROMA。这些血管异常包括过度血管通透性的倾向，导致组织水肿和血流缓慢，纤维蛋白和其他改变的基质蛋白的渗出细胞外微环境以及炎症细胞输入和流入肿瘤相关的脉管系统。此外，我们还表明雷帕霉素是肿瘤中AKT信号的有效抑制剂基质。该赠款申请有两个主要目标：（1）研究雷帕霉素对肿瘤基质和确定雷帕霉素对其抗肿瘤疗效的抗块状作用的i.npact。血管和将研究非血管基质。（2）研究关键分子对血管生成的贡献 Akt-MTOR途径可能对雷帕霉素的观察效应至关重要。 AIM 1专注于雷帕霉素的血管靶标的牙齿化。 AIM 2旨在探索雷帕霉素对非血管肿瘤基质AIM 3研究雷帕霉素对肿瘤细胞运输的抑制转移的内皮。除了检查雷帕霉素的效果外，这三个目标还包含一些对Akt-MTOR途径中个体分子的研究。提出了一个特别的重点来检查AKT 同工型和对AKT的火炬反馈在调节血管生成和内皮贩运方面为了更好地了解受雷帕霉素影响的关键调节分子以介导观察到的抗质体表型。