Inhibition of VEGF Mediated Angiogenesis by TIMP-3

TIMP-3 抑制 VEGF 介导的血管生成

• 批准号: 7258807
• 负责人: BELA ANAND-APTE
• 金额: $ 26.04万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258807
• 关键词: Angiogenesis Inhibitors; Binding; Biological Assay; Blood Vessels; Chimeric Proteins; Classification; Complex; Deletion Mutation; Endothelial Cells; Extracellular Domain; Glypican; Growth; Heparan Sulfate Proteoglycan; Heparin; Heparitin Sulfate; Hyperplasia; Immune response; Knockout Mice; LacZ Genes; Malignant Neoplasms; Maps; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Molecular; Mus; Mutation Analysis; Neoplasms; Neoplasms in Vascular Tissue; Numbers; Peptide Fragments; Physiological; Play; Principal Investigator; Range; Regulation; Role; Series; Site-Directed Mutagenesis; Structural Models; Surface; Testing; Therapeutic Intervention; Tissue Inhibitor of Metalloproteinase-3; Vascular Endothelial Growth Factors; Vascular Permeabilities; angiogenesis; base; design; extracellular; in vivo; inhibitor/antagonist; molecular modeling; mutant; neovascularization; prevent; programs; promoter; receptor; response; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Neovascularization is critical for the support of substantial tumor growth. For a wide range of tumors, a complex microvasculature accompanies the transition from hyperplasia to neoplasia, a progression from low to high-grade classification and enhanced metastatic capacity. Studies have demonstrated that a greater number of blood vessels often predict a more aggressive cancer. Thus targeting the new blood vessels of the tumor has been a promising approach for the treatment of tumors. We have recently demonstrated that Tissue Inhibitor of Metalloproteinases-3 (TIMP-3), an endogenous inhibitor of matrix metalloproteinases (MMP), is a potent inhibitor of Vascular Endothelial Growth Factor (VEGF) mediated angiogenesis. TIMP-3 can block the binding of VEGF specifically to its receptor, KDR on the surface of endothelial cells. Surprisingly, TIMP-3 mediates this angiostatic effect independent of its MMP inhibitory activity. These results led us to hypothesize that TIMP-3 is a potent endogenous angiogenesis inhibitor and plays a critical role in tumorigenesis. We propose to study the molecular modeling of TIMP-3 and KDR interactions. Based on these results, we will identify domains of TIMP-3 that have the angiostatic function but are devoid of MMP inhibitory activity. Since both TIMP-3 and VEGF bind heparan sulfate proteoglycans, we will determine the structural basis and potential role of heparin/heparan sulfate binding to the angiostatic activity of TIMP-3. We will also examine VEGF mediated angiogenesis and tumor growth in mice deficient in Timp-3. In the long term, the understanding of the molecular mechanisms of regulation of neovascularization by TIMP-3 will help in the design of therapeutic interventions to prevent unfettered growth of tumors. Specific Aims: 1. To identify the TIMP-3 and KDR domains involved in TIMP-3/KDR interaction. 2. To determine the potential role of heparin/heparan sulfate binding on the angiostatic activity of TIMP-3. 3. To determine the VEGF mediated angiogenic response and tumor growth in TIMP-3 null mice.

描述（由申请人提供）：新血管形成对于支持大量肿瘤生长至关重要。对于广泛的肿瘤，复杂的微脉管系统伴随着从增生到肿瘤的过渡，从低度分类到增强的转移能力的发展。研究表明，更多的血管通常可以预测更具侵略性的癌症。因此，针对肿瘤的新血管已成为治疗肿瘤的一种有希望的方法。我们最近证明，金属蛋白酶3（TIMP-3）的组织抑制剂是一种基质金属蛋白酶（MMP）的内源性抑制剂，是一种有效的血管内皮生长因子（VEGF）介导的血管生成的有效抑制剂。 TIMP-3可以阻止VEGF与其受体KDR在内皮细胞表面的结合。出乎意料的是，TIMP-3介导了这种血管抑制作用，而不是其MMP抑制活性。这些结果使我们假设TIMP-3是一种有效的内源性血管生成抑制剂，并且在肿瘤发生中起着至关重要的作用。我们建议研究TIMP-3和KDR相互作用的分子建模。基于这些结果，我们将确定具有血管静脉功能但没有MMP抑制活性的TIMP-3的域。由于TIMP-3和VEGF都结合了硫酸乙酰肝素蛋白聚糖，因此我们将确定肝素/硫酸乙酰肝素与TIMP-3的血管静态活性的结构基础和潜在作用。我们还将检查缺乏TIMP-3小鼠的VEGF介导的血管生成和肿瘤生长。从长远来看，TIMP-3对新血管化调控的分子机制的理解将有助于设计治疗干预措施，以防止不受约束的肿瘤生长。 具体目的： 1。确定TIMP-3和KDR域中涉及的TIMP-3/KDR相互作用。 2。确定肝素/肝素硫酸盐结合在TIMP-3的血管静脉活性上的潜在作用。 3。确定TIMP-3无效小鼠中VEGF介导的血管生成反应和肿瘤生长。