The role of angiopoietins in Wilms tumor

血管生成素在肾母细胞瘤中的作用

• 批准号: 6875355
• 负责人: JIANZHONG HUANG
• 金额: $ 13.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875355
• 关键词: Wilms' tumor; angiogenesis; angiogenesis inhibitors; angiopoietins; athymic mouse; biological signal transduction; cell proliferation; disease /disorder model; ephrins; gene expression; green fluorescent proteins; growth factor receptors; microarray technology; neoplasm /cancer genetics; pediatric neoplasm /cancer; platelet derived growth factor; protein tyrosine kinase; receptor expression; terminal nick end labeling; vascular endothelial growth factors; vascular endothelium; xenotransplantation

DESCRIPTION (provided by applicant): The Principal Investigator seeks advanced training in a mentored environment to study the role of key mediators of vessel formation and remodeling, angiopoietins-1 and -2 (Ang-1, Ang-2), in the development of vasculature in Wilms tumor. The first objective is to provide an environment for the PI, with his sponsor, Dr. Darrell Yamashiro, so that he may obtain the training in formal courses and at the laboratory bench that is needed for his development into an independent investigator. The second objective is to dissect the role of the angiopoietins in modulating the properties of Wilms tumors, using an orthotopic, metastasizing murine model of human Wilms tumor. Previous work suggests that specific features of tumor vasculature, including sprouting of new capillaries, recruitment of vascular mural cells, and endothelial integrity, are directly regulated by Ang-1 and Ang-2. In addition, angiopoietins may play a key role in the response to chronic VEGF antagonism, a novel therapeutic strategy that is extremely effective in short-term inhibition of Wilms tumor xenograft growth and metastasis. In our pilot studies, Ang-2 is highly expressed in the rapidly sprouting vasculature of Wilms tumor xenografts. When these are exposed to potent VEGF blockade, however, surviving vessels express only Ang-1, and display features linked to expression of Ang-1 (increased caliber, mural cell recruitment, enhanced integrity). Thus, we propose two specific aims: 1. We hypothesize that Ang-1 and Ang-2 play a critical role in forming vasculature with specific features in Wilms tumor. We will test this by over-expressing Ang-1, Ang-2, and a soluble form of their common Tie-2-Fc receptor in the xenograft model, and characterizing effects on vessels (endothelial/mural cell status, arterial/venous specification, and expression of angiogenesis-related genes). We will also examine the effect of these genes on the status of signaling pathways implicated in endothelial proliferation and integrity. 2. We hypothesize that angiopoietin status critically affects Wilms tumor response to VEGF blockade. We will test this by examining changes in Ang-1 and Ang-2 expression during inhibition of VEGF. We will then test the effect of superimposing VEGF blockade on Wilms tumor xenografts that overexpress these genes. Ultimately, we seek to understand the role of angiopoietins in Wilms tumor, with the goal of devising new treatments for children with aggressive cancers.

描述（由申请人提供）：首席研究人员在指导环境中寻求高级培训，以研究船舶形成和重塑，angiopoietins-1和-2（Ang-1，Ang-2）的关键介体在威尔姆斯肿瘤中脉管系统发展中的作用。第一个目标是与他的赞助商达雷尔·雅马什罗（Darrell Yamashiro）博士一起为PI提供环境，以便他可以在正式课程和实验室长凳上获得培训，并在其发展成为独立研究人员的实验室替补席上。第二个目标是使用人类Wilms肿瘤的正常，转移的鼠模型来剖析血管生成素在调节Wilms肿瘤特性中的作用。先前的工作表明，肿瘤脉管系统的特定特征，包括新毛细血管的发芽，血管壁细胞的募集和内皮完整性，受到Ang-1和Ang-2的直接调节。此外，血管生成素可能在对慢性VEGF拮抗作用的反应中起关键作用，这是一种新型的治疗策略，在短期抑制Wilms肿瘤异种移植和转移方面非常有效。在我们的试点研究中，ANG-2在Wilms肿瘤异种移植物的快速发芽脉管系统中高度表达。但是，当这些暴露于有效的VEGF封锁时，存活的血管仅表示ANG-1，并且显示与Ang-1表达的显示功能（口径增加，壁画细胞募集，增强的完整性）。因此，我们提出了两个具体目标：1。假设Ang-1和Ang-2在Wilms肿瘤中具有特定特征的脉管系统中起着关键作用。我们将通过异种移植模型中过度表达ANG-1，ANG-2和它们常见的TIE-2-FC受体的可溶形式进行测试，并表征对血管的影响（内皮/壁细胞状态，动脉/静脉/静脉/静脉表格，以及血管生成相关基因的表达）。我们还将检查这些基因对涉及内皮增殖和完整性的信号通路状态的影响。 2。我们假设血管生成素状态严重影响Wilms肿瘤对VEGF封锁的反应。我们将通过在抑制VEGF期间检查ANG-1和ANG-2表达的变化来测试这一点。然后，我们将测试叠加VEGF阻断对过表达这些基因的Wilms肿瘤异种移植物的影响。最终，我们试图了解血管生物在威尔姆斯肿瘤中的作用，目的是为患有侵略性癌症的儿童制定新的治疗方法。