This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recently, we characterized a unique avb3 integrin ligand representing a cryptic epitope of collagen-IV. This epitope (HUIV26) binds avb3 and is associated with increased melanoma metastasis and angiogenesis. The signaling mechanisms triggered by interactions with this epitope in endothelial cells are not understood. We will focus on characterizing a novel mechanism of avb3 activation in endothelium that regulates tumor angiogenesis. Preliminary studies suggest that tumors expressing avb3 exhibit a growth advantage in vivo but not in vitro and these tumors were associated with increased angiogenesis. Surprisingly, reduction in avb3 or inhibition of avb3-mediated binding to the HUIV26 epitope increased expression of insulin-like growth factor binding protein-4 (IGFBP-4). This novel downstream target of HUIV26/ avb3 interactions supports the hypothesis that IGFBP-4 may be endogenous angiogenesis inhibitor that is suppressed in cells in which avb3 is activated. We will test the hypothesis that endothelial cell avb3 binding to denatured collagen suppresses IGFBP-4, which increases the angiogenic response. This proposal is designed to examine three central objectives. First, we will examine the ability of endothelial cell avb3 to regulate IGFBP-4 and other IGFBPs in vitro and in vivo. In addition, we will examine the contributions of PI3Kinase/Akt pathway, and MAP Kinase pathway in this process. We will assess whether the circulating and tissue levels of IGFBPs correlate with angiogenesis in vivo. Second, we will evaluate the biochemical and cellular effects of IGFBPs on endothelial cell behavior. Finally, we will examine the biological effects of IGFBPs on cytokine and tumor-induced angiogenesis in vivo.
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