The role of angiopoietins in Wilms tumor

描述(由申请人提供)：首席调查员寻求在指导环境中接受高级培训，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展中的作用。第一个目标是在他的赞助人Darrell Yamashiro博士的帮助下，为PI提供一个环境，以便他可以在正规课程和实验室工作台上获得发展为独立调查员所需的培训。第二个目标是利用人肾母细胞瘤的原位转移小鼠模型，剖析血管生成素在调节肾母细胞瘤特性中的作用。以前的工作表明，肿瘤血管的特殊功能，包括新的毛细血管的萌发，血管壁细胞的募集，以及内皮的完整性，都直接受到Ang-1和Ang-2的调节。此外，血管生成素可能在慢性血管内皮生长因子拮抗反应中发挥关键作用，这是一种新的治疗策略，在短期内抑制肾母细胞瘤异种移植瘤的生长和转移非常有效。在我们的先导研究中，Ang-2在Wilms肿瘤异种移植瘤快速萌发的血管系统中高度表达。然而，当这些血管暴露在强有力的血管内皮生长因子阻滞剂下时，存活的血管只表达Ang-1，并表现出与Ang-1表达相关的特征(管径增加、壁细胞募集、完整性增强)。因此，我们提出了两个特定的目标：1.我们假设Ang-1和Ang-2在肾母细胞瘤中形成具有特定特征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及其常见的Tie-2-Fc受体的可溶性形式来测试这一点，并表征对血管的影响(内皮/壁细胞状态、动脉/静脉规范以及血管生成相关基因的表达)。我们还将研究这些基因对与内皮细胞增殖和完整性有关的信号通路状态的影响。2.我们推测血管生成素状态是影响肾母细胞瘤对血管内皮生长因子拮抗剂反应的重要因素。我们将通过检测在抑制血管内皮生长因子的过程中Ang-1和Ang-2表达的变化来测试这一点。然后，我们将测试叠加血管内皮生长因子阻滞剂对过度表达这些基因的Wilms肿瘤移植瘤的影响。最终，我们试图了解血管生成素在肾母细胞瘤中的作用，目标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.