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.
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