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）：冯·希皮（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。 它的潜在遗传缺陷是在VHL肿瘤抑制基因中。 因此，VHL突变体代表了研究肿瘤诱导的血管生成的绝佳系统。 我们已经确定了一种进化保守的新型突变机制，该机制导致VHL突变体细胞表面上的FGF受体（FGFR）过度蓄能。 在果蝇，恶性肾细胞癌（RCC）培养物中观察到这种现象，并且可能在人类微血管内皮细胞（HMVEC）中观察到。 还注意到，过度耗尽的FGFR导致ETS1活性的异常迁移和诱导，其功能与转移和血管生成有关。 我们以前已经发现，VHL的功能可能是由另一个肿瘤抑制基因NM23介导的。 基于这些初步数据，提出了一种新型的细胞内机制，该机制是基于VHL和NM23突变中FGFR积累表型的基础（如人类VHL疾病患者和果蝇发育突变体中，以及这种异常信号事件如何通过ETS1通过血管生成过程中调节细胞运动。 我们将利用体外和体内模型系统，并采用跨物种比较研究来剖析信号传导机制。 AIM 1将剖析导致FGFR过度积累的囊泡传输途径。 AIM 2将分析使用3维共培养系统的VHL，FGFR和ETS1在调节血管生成中的作用。 AIM 3将检查VHL与NM23相关的新功能。 AIM 4将采用基因敲除小鼠来检验以下假设：VHL病患者内皮细胞中VHL杂合突变在该疾病高度血管化的肿瘤性特征中起着重要作用。