The role of angiopoietins in Wilms tumor

描述（由申请人提供）：首席研究员寻求在有指导的环境中接受高级培训，研究血管形成和重塑的关键介质血管生成素-1和-2 （Ang-1, Ang-2）在Wilms肿瘤血管系统发展中的作用。第一个目标是为PI及其赞助人Darrell Yamashiro博士提供一个环境，使他能够在正式课程和实验室工作台上获得发展为独立研究者所需的培训。第二个目的是剖析血管生成素在调节肾母细胞瘤特性中的作用，使用人类肾母细胞瘤的原位转移小鼠模型。先前的研究表明，肿瘤血管系统的特定特征，包括新毛细血管的萌芽、血管壁细胞的募集和内皮的完整性，都是由Ang-1和Ang-2直接调节的。此外，血管生成素可能在慢性VEGF拮抗反应中发挥关键作用，这是一种新的治疗策略，在短期抑制Wilms肿瘤异种移植生长和转移方面非常有效。在我们的初步研究中，Ang-2在肾母细胞瘤异种移植物快速发芽的血管中高度表达。然而，当这些血管暴露于有效的VEGF阻断中时，存活的血管仅表达Ang-1，并表现出与Ang-1表达相关的特征（直径增加，壁细胞募集，完整性增强）。因此，我们提出两个具体目标：1。我们假设在Wilms肿瘤中，Ang-1和Ang-2在形成具有特定特征的血管系统中起关键作用。我们将通过在异种移植物模型中过表达Ang-1、Ang-2和它们共同的Tie-2-Fc受体的可溶性形式来验证这一点，并表征对血管的影响（内皮/壁细胞状态、动脉/静脉规范和血管生成相关基因的表达）。我们还将研究这些基因对内皮细胞增殖和完整性相关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阻断的反应。我们将通过检测VEGF抑制过程中Ang-1和Ang-2表达的变化来验证这一点。然后，我们将测试叠加VEGF阻断对过度表达这些基因的Wilms肿瘤异种移植物的影响。最终，我们试图了解血管生成素在Wilms肿瘤中的作用，目的是为患有侵袭性癌症的儿童设计新的治疗方法。

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.