Spatial and Temporal Regulation of Angiogenesis

血管生成的时空调节

• 批准号: 8079648
• 负责人: HAROLD FISHER DVORAK
• 金额: $ 160.63万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079648
• 关键词: Spatial; Temporal; Regulation; Angiogenesis

DESCRIPTION (provided by applicant): This PPG focuses on the spatial and temporal regulation of tumor angiogenesis, associated vascular hyperpermeability, and stroma generation. The overriding hypothesis is that tumor vessels and stroma are essential for tumor growth and survival and that they offer attractive targets for tumor therapy. The goal is to achieve a much better understanding of the pro- and anti-angiogenic forces that regulate these processes in order to find novel points of attack that can prevent tumor angiogenesis and stroma formation and deprive tumors of existing vessels and stroma. Four interactive Projects are proposed: Project 1 will focus on the role of TR3/Nur77, an orphan transcription factor critical for the induction of VEGF-A-induced angiogenesis and vascular permeability. It will also elucidate the signaling pathways by which VEGF-A regulates TR3/Nur77's expression and transcriptional activation. Project 2 will investigate the effects of rapamycin on the Akt-mTOR signaling pathway and its effects on tumor stroma that lead to tumor growth inhibition. The Hypothesis is that rapamycin inhibits tumor angiogenesis more potently than it inhibits tumor cells and that these anti-stromal effects mediate much of rapamycin's anti-tumor efficacy. Aims will seek to identify the vascular targets of rapamycin, the molecular changes in the Akt-mTOR signaling pathway that mediate its anti-angiogenic effects, and explore the role of Akt signaling on tumor cell trafficking across vascular endothelium. Project 3 will investigate the role of estrogen and its receptor (ER?) on angiogenesis and other aspects of stroma generation that favor systemic angiogenesis and tumor growth. Further, it will investigate the mechanisms by which estrogen-ER? interactions lead to bone marrow mobilization, accumulation in tumor sites, and differentiation into tumor-supporting myofibroblasts and histiocytes. Project 4 will investigate the effectiveness of the three type 1 repeats (3TSR) component of thrombospondin-1 (TSP-1), in combination with TRAIL receptor agonist antibodies, in inhibiting tumor growth. It will also identify the receptors and signaling molecules that mediate the anti-angiogenic activity of TSP-1 and 3TSR. Together these preclinical studies will contribute much to an understanding of the signaling pathways by which tumors induce angiogenesis and stroma formation and are expected to identify pathways and molecules that can be used as therapeutic targets in cancer treatment.

描述（由申请人提供）：该PPG着重于肿瘤血管生成，相关的血管过度过度性和基质产生的空间和时间调节。压倒性的假设是肿瘤血管和基质对于肿瘤生长和生存至关重要，并且为肿瘤治疗提供了有吸引力的靶标。目的是更好地了解调节这些过程的促和抗血管生成力，以找到可以防止肿瘤血管生成和基质形成的新型攻击点，并剥夺现有血管和基质的肿瘤。提出了四个互动项目：项目1将集中于TR3/NUR77的作用，TR3/NUR77的作用是诱导VEGF-A诱导的血管生成和血管渗透性至关重要的孤儿转录因子。它还将阐明VEGF-A调节TR3/NUR77的表达和转录激活的信号通路。项目2将研究雷帕霉素对AKT-MTOR信号通路及其对肿瘤基质的影响，从而导致肿瘤生长抑制。假设是，雷帕霉素比抑制肿瘤细胞更有效地抑制肿瘤血管生成，并且这些抗抑制作用介导了雷帕霉素的抗肿瘤疗效的大部分。目标将寻求鉴定雷帕霉素的血管靶标，雷帕霉素是介导其抗血管生成作用的Akt-MTOR信号传导途径的分子变化，并探讨了Akt信号传导对肿瘤细胞运输跨血管内皮细胞的作用。项目3将研究雌激素及其受体（ER？）对有利于全身性血管生成和肿瘤生长的基质生成的血管生成和其他方面的作用。此外，它将研究雌激素-ER的机制？相互作用导致骨髓动员，肿瘤部位的积累以及分化为肿瘤支持的肌纤维细胞和组织细胞。项目4将研究血小板素-1（TSP-1）的三种1型重复（3TSR）分量与径向受体受体激动剂抗体在抑制肿瘤生长中的有效性。它还将鉴定介导TSP-1和3TSR的抗血管生成活性的受体和信号分子。总之，这些临床前研究将有助于了解肿瘤诱导血管生成和基质形成的信号通路，并有望鉴定可以用作癌症治疗中可以用作治疗靶标的途径和分子。