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

胰岛素样生长因子结合蛋白 (IGFBPS) 在血管生成中的作用

• 批准号: 7959661
• 负责人: PETER C. BROOKS
• 金额: $ 18.8万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959661
• 关键词: Angiogenesis Inhibitors; Binding; Biochemical; Biological; Biology; Blood Vessels; Cells; Centers of Research Excellence; Collagen; Collagen Type IV; Computer Retrieval of Information on Scientific Projects Database; Endothelial Cells; Endothelium; Epitopes; Exhibits; Funding; Grant; Growth; In Vitro; Institution; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth-Factor-Binding Proteins; Integrins; Ligands; Mediating; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Pathway interactions; Process; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Testing; Tissues; Tumor Angiogenesis; United States National Institutes of Health; angiogenesis; cell behavior; cytokine; design; in vivo; melanoma; novel; response; tumor

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 最近，我们的特点是一个独特的avb 3整合素配体代表一个隐蔽的表位的胶原蛋白-IV。该表位（HUIV 26）结合avb 3，并与增加的黑色素瘤转移和血管生成相关。内皮细胞中与该表位相互作用触发的信号传导机制尚不清楚。我们将集中于描述血管内皮中avb 3激活调节肿瘤血管生成的新机制。初步研究表明，表达avb 3的肿瘤在体内表现出生长优势，而在体外则没有，并且这些肿瘤与血管生成增加有关。令人惊讶的是，avb 3的减少或avb 3介导的与HUIV 26表位的结合的抑制增加了胰岛素样生长因子结合蛋白-4（IGFBP-4）的表达。HUIV 26/avb 3相互作用的这种新型下游靶点支持IGFBP-4可能是内源性血管生成抑制剂的假设，该抑制剂在avb 3被激活的细胞中受到抑制。我们将检验内皮细胞avb 3与变性胶原蛋白结合抑制IGFBP-4，从而增加血管生成反应的假设。本建议旨在审查三个中心目标。 首先，我们将在体外和体内检测内皮细胞avb 3调节IGFBP-4和其他IGFBPs的能力。 此外，我们还将研究PI 3激酶/Akt通路和MAP激酶通路在这一过程中的作用。我们将评估IGFBPs的循环和组织水平是否与体内血管生成相关。 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在体内对细胞因子和肿瘤诱导的血管生成的生物学效应。