MOLECULAR STUDIES OF VPF/VEGF

VPF/VEGF 的分子研究

• 批准号: 2390843
• 负责人: Kevin P. Claffey
• 金额: $ 13.16万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-05 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2390843
• 关键词: angiogenesis; athymic mouse; biological signal transduction; carcinogenesis; cell type; disease /disorder model; embryogenesis; gene expression; genetically modified animals; growth factor; growth factor receptors; messenger RNA; molecular cloning; neoplastic growth; northern blottings; transfection; vascular endothelial growth factors; vascular endothelium; vascular endothelium permeability

The long-term objectives for this proposal are to identify the molecular mechanisms of tumor-related angiogenesis with the purpose of developing therapeutic approaches to reducing the morbidity and mortality associated with human cancers. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) has been identified as an endothelial growth factor which is widely expressed in important human cancers including glioblastoma multiforme, gastrointestinal adenocarcinoma, Kaposi's sarcoma, breast carcinoma and renal cell carcinoma. Expression of VPF/VEGF also occurs in other human diseases which demonstrate vascular proliferation and hyperpermeability; namely, rheumatoid arthritis, psoriasis and diabetic retinopathy. This proposal will address two basic questions: 1. What is the role of VPF/VEGF in tumor-associated angiogenesis and tumor growth? 2. What role does VPF/VEGF play in the primary angiogenesis of normal development? The role of VPF/VEGF in tumor- related angiogenesis will be tested directly in vivo with rodent tumor models. Tumor cells will be developed that overexpress VPF/VEGF or whose expression of VPF/VEGF has been inhibited. Several tumor cell lines express variable levels of VPF/VEGF under hypoxic conditions, an important phenomenon occurring during tumor progression. Surprisingly, the ability of different tumor cell types to respond to hypoxia by induction of VPF/VEGF production directly correlates to their tumorigenicity in nude mice. Stable transfected tumor cells expressing increased or reduced levels of VPF/VEGF will be implanted in vivo and tumor growth rate, histology, vascularization and expression of VPF/VEGF and VPF/VEGF receptors will be evaluated. These tumor models will define the role of VPF/VEGF in tumor development, particularly addressing whether the expression of VPF/VEGF is a key cytokine which positively affects tumor growth and angiogenesis. The role of VPF/VEGF in normal primary angiogenesis occurring in mammalian development will be evaluated in vivo by developing transgenic animal models which either repress or overexpress VPF/VEGF. These transgenic lines will help to delineate the function of VPF/VEGF in relation to both temporal and spatial events required for proper adipose tissue and organ development. Collectively, these experiments will define the function of VPF/VEGF in tumor growth and normal angiogenesis and will determine whether VPF/VEGF is an appropriate target for therapeutic intervention in human pathologies such as cancer.

该提案的长期目标是确定分子 肿瘤相关血管生成的机制，目的是开发 降低相关发病率和死亡率的治疗方法 与人类癌症。血管通透因子/血管内皮 生长因子（VPF/VEGF）已被确定为内皮生长因子 在重要的人类癌症中广泛表达的因子，包括 多形性胶质母细胞瘤、胃肠道腺癌、卡波西氏病 肉瘤、乳腺癌和肾细胞癌。 VPF/VEGF的表达 也发生在其他人类疾病中，这些疾病表明血管 增殖和渗透性过高；即类风湿性关节炎， 牛皮癣和糖尿病视网膜病变。该提案将解决两个基本问题 问题： 1. VPF/VEGF在肿瘤相关性中的作用是什么？ 血管生成和肿瘤生长？ 2. VPF/VEGF在肿瘤发生中起什么作用 正常发育的原发性血管生成？ VPF/VEGF 在肿瘤中的作用 相关的血管生成将直接在啮齿动物肿瘤体内进行测试 模型。肿瘤细胞将发育成过度表达 VPF/VEGF 或其 VPF/VEGF的表达受到抑制。几种肿瘤细胞系 在缺氧条件下表达不同水平的 VPF/VEGF，这是一个重要的 肿瘤进展过程中发生的现象。令人惊讶的是，有能力 不同肿瘤细胞类型通过诱导对缺氧做出反应 VPF/VEGF 的产生与其裸体内的致瘤性直接相关 老鼠。稳定转染的肿瘤细胞表达增加或减少 植入体内的VPF/VEGF水平和肿瘤生长速度， VPF/VEGF 和 VPF/VEGF 的组织学、血管化和表达 将评估受体。这些肿瘤模型将定义 VPF/VEGF 在肿瘤发展中的作用，特别是解决是否 VPF/VEGF的表达是对肿瘤产生积极影响的关键细胞因子 生长和血管生成。 VPF/VEGF 在正常原发性中的作用 哺乳动物发育中发生的血管生成将在体内进行评估 通过开发抑制或过度表达的转基因动物模型 VPF/VEGF。这些转基因系将有助于描述其功能 VPF/VEGF 与所需的时间和空间事件有关 适当的脂肪组织和器官发育。总的来说，这些 实验将明确 VPF/VEGF 在肿瘤生长和 正常的血管生成，并将确定 VPF/VEGF 是否合适 癌症等人类病理学治疗干预的目标。