VHL and FGFR signaling in angiogenesis

血管生成中的 VHL 和 FGFR 信号传导

• 批准号: 6827684
• 负责人: TIEN HSU
• 金额: $ 29.93万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827684
• 关键词: Drosophilidae; Von Hippel Lindau syndrome; angiogenesis; biological signal transduction; cell migration; enzyme activity; epidermal growth factor; fibroblast growth factor; gene expression; gene mutation; genetically modified animals; growth factor receptors; hemangioma; intracellular transport; laboratory mouse; mixed tissue /cell culture; molecular oncology; neoplasm /cancer blood supply; neoplasm /cancer genetics; tumor suppressor genes; vascular endothelium; vesicle /vacuole; vimentin; wound healing

DESCRIPTION (provided by applicant): The von HippeI-Lindau (VHL) syndrome is a hereditary disease that is characterized by the development of highly vascularized tumors. Its underlying genetic defect is in the VHL tumor suppressor gene. The VHL mutant therefore represents an excellent system for studying the tumor-induced angiogenesis. We have identified an evolutionarily conserved novel mutational mechanism that leads to FGF receptor (FGFR) over-accumulation on the cell surface in VHL mutants. This phenomenon is observed in Drosophila, in the malignant renal cell carcinoma (RCC) culture, and likely in the human microvascular endothelial cells (HMVECs). It was also noted that the over-accumulated FGFR leads to aberrant cell migration and induction of Ets1 activity, whose function has been linked to metastasis and angiogenesis. We have previously found that the function of VHL is likely mediated by another tumor suppressor gene nm23. Based on these preliminary data, a novel intracellular mechanism is proposed that underlies the FGFR accumulation phenotype in VHL and nm23 mutations (as in human VHL disease patients and in Drosophila developmental mutant) and how this aberrant signaling event, via Ets1, can modulate cell motility during angiogenesis. We will utilize in vitro and in vivo model systems and employ cross-species comparative studies to dissect the signaling mechanisms. Aim 1 will dissect the vesicle transport pathway that results in FGFR over-accumulation. Aim 2 will analyze the role of VHL, FGFR, and Ets1 in modulating angiogenesis, employing a 3-dimensional co-culture system. Aim 3 will examine the novel function of VHL in relation to Nm23. Aim 4 will employ knockout mice to test the hypothesis that VHL heterozygous mutation in endothelial cells in the VHL disease patients play an important role in the disease' highly vascularized tumorigenic characteristics.

描述（由申请人提供）：von HippeI-Lindau（VHL）综合征是一种遗传性疾病，其特征在于高度血管化肿瘤的发展。 其潜在的遗传缺陷是VHL肿瘤抑制基因。 因此，VHL突变体是研究肿瘤诱导的血管生成的一个很好的系统。 我们已经确定了一个进化上保守的新的突变机制，导致FGF受体（FGFR）过度积累的VHL突变体的细胞表面上。 这种现象在果蝇、恶性肾细胞癌（RCC）培养物中观察到，并且可能在人微血管内皮细胞（HMVEC）中观察到。 还注意到，过度积累的FGFR导致异常细胞迁移和Ets 1活性的诱导，Ets 1活性的功能与转移和血管生成有关。 我们以前发现VHL的功能可能是由另一个肿瘤抑制基因nm 23介导的。 基于这些初步数据，提出了一种新的细胞内机制，VHL和nm 23突变（如在人类VHL疾病患者和果蝇发育突变体）的FGFR积累表型的基础，以及这种异常信号事件如何通过Ets 1调节血管生成过程中的细胞运动。 我们将利用体外和体内模型系统，并采用跨物种的比较研究来剖析信号机制。 目的1将剖析导致FGFR过度积累的囊泡转运途径。 目的2将采用三维共培养系统分析VHL、FGFR和Ets 1在调节血管生成中的作用。 目的3将研究VHL与Nm 23相关的新功能。 目的4：利用基因敲除小鼠验证VHL患者内皮细胞VHL杂合突变在VHL疾病的高度血管化致瘤特征中起重要作用的假设。