VHL and FGFR signaling in angiogenesis

血管生成中的 VHL 和 FGFR 信号传导

• 批准号: 6906477
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906477
• 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，其特征是形成高度血管化的肿瘤。 其潜在的遗传缺陷在于 VHL 肿瘤抑制基因。 因此，VHL 突变体代表了研究肿瘤诱导的血管生成的优秀系统。 我们发现了一种进化上保守的新突变机制，该机制导致 VHL 突变体细胞表面 FGF 受体 (FGFR) 过度积累。 这种现象在果蝇、恶性肾细胞癌 (RCC) 培养物中以及可能在人类微血管内皮细胞 (HMVEC) 中观察到。 还值得注意的是，过度积累的 F​​GFR 会导致异常细胞迁移和 Ets1 活性的诱导，而 Ets1 的功能与转移和血管生成有关。 我们之前发现VHL的功能很可能是由另一个抑癌基因nm23介导的。 基于这些初步数据，提出了一种新的细胞内机制，该机制是 VHL 和 nm23 突变（如人类 VHL 疾病患者和果蝇发育突变体）中 FGFR 积累表型的基础，以及这种异常信号传导事件如何通过 Ets1 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比较研究来剖析信号传导机制。 目标 1 将剖析导致 FGFR 过度积累的囊泡转运途径。 目标 2 将采用 3 维共培养系统分析 VHL、FGFR 和 Ets1 在调节血管生成中的作用。 目标 3 将研究 VHL 与 Nm23 相关的新功能。 目标 4 将采用基因敲除小鼠来检验 VHL 疾病患者内皮细胞中的 VHL 杂合突变在该疾病的高度血管化致瘤特征中发挥重要作用的假设。