PLASMIN SYSTEM AND IGF FUNCTION IN OSTEOSARCOMA

胰岛素样生长因子（IGFs）产生并影响几乎所有 包括骨细胞。 IGFs存在于血液和 与特异性IGF结合蛋白（IGFBPs）结合的间隙空间。 IGFBPs可以通过抑制IGFs在正常骨和肿瘤骨中的作用， 与IGFS形成无生物活性的复合物。 生理 IGFs从IGFBP中释放的机制仍不清楚。 因此，本项目的主要目标是了解如何 细胞旁蛋白酶影响IGF作用。 骨肉瘤细胞分泌 将纤溶酶原激活为纤溶酶（纤溶酶 系统）。 用条件培养基进行初步实验， 骨肉瘤细胞建立了IGF中纤溶酶系统的参与 activation. 该项目的目的是扩展这些数据， 证明PA-纤溶酶原-纤溶酶酶级联反应 也是在细胞水平上。 为此，我们建议使用人类 骨肉瘤细胞系作为我们的模型系统。IGF作用参数， 例如细胞结合，生长和分化，将在 关于通过纤溶酶系统调节IGF-BP复合物的研究 IGFs从IGFBP解离为IGF的各个步骤中， 被执行。 在调查过程中，我们将测试 IGF激活位点位于细胞表面的假设， 它的附近。 最后，纤溶酶之间的相互作用 系统，IGF和IGFBP的基因表达和肽 分泌，也将建立。LBE的调查结果， 研究将提供一个基本的洞察力的调节IGF行动 不仅适用于肿瘤细胞类型，而且也适用于正常细胞。

Insulin-like growth factors (IGFs) are produced by and affect nearly all types of cells, including bone cells. IGFs exist in blood and in the interstitial space bound to specific IGF-binding proteins (IGFBPs). IGFBPs can inhibit the action of IGFs in normal and neoplastic bone by forming biologically inactive complexes with IGFS. The physiological mechanism(s) by which IGFs are released from IGFBP remains unclear. Therefore, the major goal of this project is to understand how paracellular proteases affect IGF action. Osteosarcoma cells secrete plasminogen activators which activate plasminogen to plasmin (plasmin system). Preliminary experiments conducted with media conditioned by osteosarcoma cells establish an involvement of plasmin system in IGF activation. The intent of this project is to extend these data and demonstrate that the PA-plasminogen-plasmin enzymatic cascade operates also at the cellular level. To this end, we propose to use human osteosarcoma cell lines as our model system. Parameters of IGF action, e.g. cell binding, growth and differentiation, will be determined in regard to regulation of the IGF-BP complex by the plasmin system Studies of the various steps in the dissociation of IGFs from IGFBP to IGF will be performed. During the course of these investigations, we will test the hypothesis that the site of IGF activation is at the cell surface or its immediate vicinity. Finally, the interactions among the plasmin system, IGF, and IGFBP as regards to the gene expression and peptide secretion, will also be established. lbe findings from this proposed research will provide a basic insight into the regulation of IGF action applicable not only to neoplastic cell types but normal cells as well.