Spatial and Temporal Regulation of Angiogenesis

描述（由申请人提供）：该PPG侧重于肿瘤血管生成、相关血管通透性过高和基质生成的空间和时间调节。最重要的假设是肿瘤血管和间质对于肿瘤生长和存活是必不可少的，并且它们为肿瘤治疗提供了有吸引力的靶点。我们的目标是更好地理解调节这些过程的促血管生成和抗血管生成力量，以找到新的攻击点，可以防止肿瘤血管生成和基质形成，并剥夺肿瘤现有的血管和基质。提出了四个互动项目：项目1将重点关注TR 3/Nur 77的作用，TR 3/Nur 77是一种孤儿转录因子，对诱导VEGF-A诱导的血管生成和血管通透性至关重要。它还将阐明VEGF-A调节TR 3/Nur 77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信号通路的影响及其对肿瘤基质的影响，从而导致肿瘤生长抑制。该假说认为雷帕霉素抑制肿瘤血管生成比抑制肿瘤细胞更有效，并且这些抗基质效应介导了雷帕霉素的大部分抗肿瘤功效。目的将寻求确定雷帕霉素的血管靶点，介导其抗血管生成作用的Akt-mTOR信号通路中的分子变化，并探索Akt信号在肿瘤细胞跨血管内皮运输中的作用。项目3将研究雌激素及其受体（ER？）血管生成和基质生成的其他方面，有利于系统性血管生成和肿瘤生长。此外，它将调查的机制，雌激素-ER？相互作用导致骨髓动员、在肿瘤部位的积聚和分化成肿瘤支持性肌成纤维细胞和组织细胞。项目4将研究血小板反应蛋白-1（TSP-1）的三种1型重复序列（3 TSR）组分与TRAIL受体激动剂抗体联合抑制肿瘤生长的有效性。它还将确定介导TSP-1和3 TSR的抗血管生成活性的受体和信号分子。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，并有望确定可用作癌症治疗靶点的通路和分子。

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.