ROLE OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS (IGFBPS) IN ANGIOGENESIS

这个子项目是众多研究子项目之一

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 alphavbeta3 ligand representing a cryptic epitope of collagen-IV. This epitope (HUIV26) binds alphavbeta3 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 alphavbeta3 activation in endothelium that regulates tumor angiogenesis. Preliminary studies suggest that tumors expressing alphavbeta3 exhibit a growth advantage in vivo but not in vitro and these tumors were associated with increased angiogenesis. Surprisingly, reduction in alphavbeta3 or inhibition of alphavbeta3-mediated binding to the HUIV26 epitope increased expression of insulin-like growth factor binding protein-4 (IGFBP-4). This novel downstream target of HUIV26/ alphavbeta3 interactions supports the hypothesis that IGFBP-4 may be endogenous angiogenesis inhibitor that is suppressed in cells in which alphavbeta3 is activated. We will test the hypothesis that endothelial cell alphavbeta3 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 alphavbeta3 to regulate IGFBP-4 and other IGFBPs in vitro and in vivo. In addition, we will examine the contributions of PI3Kinase/Akt pathway, and MAPKinase pathway in this process. We will assess whether the circulating and tissue levels of IGFBPs correlate with angiogenesis in the chick embryo. 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 the chick embryo.