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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 最近，我们鉴定了一种独特的α-β3配体，它代表了IV型胶原的隐蔽表位。该表位(HUIV26)与αvbeta3结合，与黑色素瘤转移和血管生成增加有关。内皮细胞中与该表位相互作用所触发的信号机制尚不清楚。我们将重点研究一种新的调节肿瘤血管生成的内皮细胞αvbeta3激活机制。初步研究表明，表达alphavbeta3的肿瘤在体内显示出生长优势，但在体外不显示，这些肿瘤与增加血管生成有关。令人惊讶的是，Alphavbeta3的减少或Alphavbeta3介导的与HUIV26表位的结合被抑制会增加胰岛素样生长因子结合蛋白-4(IGFBP-4)的表达。这个新的HUIV26/alphavbeta3相互作用的下游靶点支持了IGFBP-4可能是内源性血管生成抑制因子的假设，在alphavbeta3被激活的细胞中，IGFBP-4可能被抑制。我们将测试内皮细胞αvbeta3与变性胶原结合抑制IGFBP-4的假设，IGFBP-4可增加血管生成反应。这项提案旨在审查三个核心目标。首先，我们将在体外和体内检测内皮细胞αvbeta3调节IGFBP-4和其他IGFBPs的能力。此外，我们还将研究PI3Kinase/Akt通路和MAPKinase通路在这一过程中的作用。我们将评估循环和组织中IGFBPs的水平是否与鸡胚胎中的血管生成相关。其次，我们将评估IGFBPs对内皮细胞行为的生化和细胞效应。最后，我们将研究IGFBPs在鸡胚胎细胞因子和肿瘤诱导的血管生成中的生物学作用。

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.