Inhibition of VEGF Mediated Angiogenesis by TIMP-3

TIMP-3 抑制 VEGF 介导的血管生成

基本信息

批准号：
7646321
负责人：
BELA ANAND-APTE
金额：
$ 28.93万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
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/7646321
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 Molecular Models Mus Mutation Analysis Neoplasms Neoplasms in Vascular Tissue Peptide Fragments Physiologic Neovascularization Play Principal Investigator 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

项目摘要

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肿瘤的实质性生长至关重要。对于多种肿瘤，复杂的微血管系统伴随着从增生到瘤形成的转变，从低级到高级分类的进展以及增强的转移能力。研究表明，更多的血管通常预示着更具侵袭性的癌症。因此，靶向肿瘤的新血管已成为治疗肿瘤的一种有前途的方法。我们最近证明，金属蛋白酶组织抑制剂-3 (TIMP-3) 是一种基质金属蛋白酶 (MMP) 内源性抑制剂，是血管内皮生长因子 (VEGF) 介导的血管生成的有效抑制剂。 TIMP-3可以特异性阻断VEGF与其内皮细胞表面受体KDR的结合。令人惊讶的是，TIMP-3 介导这种血管抑制作用，与其 MMP 抑制活性无关。这些结果使我们推测 TIMP-3 是一种有效的内源性血管生成抑制剂，在肿瘤发生中发挥着关键作用。我们建议研究 TIMP-3 和 KDR 相互作用的分子模型。基于这些结果，我们将鉴定具有血管抑制功能但缺乏 MMP 抑制活性的 TIMP-3 结构域。由于 TIMP-3 和 VEGF 均结合硫酸乙酰肝素蛋白聚糖，因此我们将确定肝素/硫酸乙酰肝素结合 TIMP-3 血管抑制活性的结构基础和潜在作用。我们还将检查 Timp-3 缺陷小鼠中 VEGF 介导的血管生成和肿瘤生长。从长远来看，了解 TIMP-3 调节新血管形成的分子机制将有助于设计治疗干预措施，以防止肿瘤不受限制的生长。具体目标： 1. 识别参与 TIMP-3/KDR 相互作用的 TIMP-3 和 KDR 结构域。 2.确定肝素/硫酸乙酰肝素结合对TIMP-3的血管抑制活性的潜在作用。 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。