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

• 批准号: 8378437
• 负责人: HAROLD FISHER DVORAK
• 金额: $ 29.49万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-13 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8378437
• 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

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.

我们已经发现Akt信号传导在肿瘤血管中的一些更显著的异常中起作用， [咒语]这些血管异常包括过度血管渗透性的倾向，导致 组织水肿和血流缓慢，纤维蛋白和其他基质蛋白外渗，改变了组织的结构。 细胞外微环境，以及炎性细胞进出肿瘤相关微环境的运输。 脉管系统此外，我们还发现雷帕霉素是肿瘤中Akt信号传导的有效抑制剂， 基质。这项拨款申请有两个主要目标：（1）研究雷帕霉素对肿瘤基质的影响， 以确定雷帕霉素的抗基质效应对其抗肿瘤功效的影响。血管和 将研究非血管基质。(2)研究血管生成中关键分子的作用， Akt-mTOR通路可能对观察雷帕霉素的作用至关重要。目标1的重点是 鉴定雷帕霉素的血管靶点。目的2：探讨雷帕霉素对人肝癌细胞凋亡的影响， 目的3研究雷帕霉素对肿瘤细胞跨血管运输的抑制作用。 内皮细胞在转移中的作用。除了检测雷帕霉素的作用外，这三个目标都包含一些 研究Akt-mTor途径中的单个分子。一个特别的重点是提出检查Akt 同种型和TORCH反馈Akt在调节血管生成和内皮细胞运输中的作用 为了更好地了解受雷帕霉素影响的关键调节分子， 观察到抗基质表型。