The role of angiopoietins in Wilms tumor

描述（由申请人提供）：主要研究者寻求在指导环境中进行高级培训，以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）在肾母细胞瘤血管系统发育中的作用。第一个目标是为PI及其申办者Darrell Yamashiro博士提供一个环境，以便他可以获得正式课程和实验室工作台的培训，这是他发展成为独立研究者所需的。第二个目的是使用原位转移的人肾母细胞瘤小鼠模型，剖析血管生成素在调节肾母细胞瘤性质中的作用。以前的工作表明，肿瘤血管系统的具体特征，包括新毛细血管的发芽，血管壁细胞的募集和内皮的完整性，直接由Ang-1和Ang-2调节。此外，血管生成素可能在对慢性VEGF拮抗作用的反应中发挥关键作用，这是一种在短期抑制Wilms肿瘤异种移植物生长和转移方面极其有效的新型治疗策略。在我们的初步研究中，Ang-2在肾母细胞瘤异种移植物的快速发芽血管中高度表达。然而，当这些血管暴露于有效的VEGF阻断时，存活的血管仅表达Ang-1，并显示与Ang-1表达相关的特征（增加的口径、壁细胞募集、增强的完整性）。因此，我们提出两个具体目标：1。我们推测Ang-1和Ang-2在肾母细胞瘤中具有特异性的血管形成中起关键作用。我们将通过在异种移植模型中过度表达Ang-1、Ang-2和它们共同的Tie-2-Fc受体的可溶形式，并表征对血管的影响（内皮/壁细胞状态、动脉/静脉特化和血管生成相关基因的表达）来测试这一点。我们还将研究这些基因对内皮细胞增殖和完整性相关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肾母细胞瘤对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阻断对过表达这些基因的肾母细胞瘤异种移植物的影响。最终，我们试图了解血管生成素在肾母细胞瘤中的作用，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.