TRANSFORMATION DEPENDENT GENE EXPRESSION IN GLIOMA CELLS

拟议项目的目的是研究 胶质瘤细胞的恶性行为。我们要研究的是 外周苯二氮卓类受体与原癌基因的激活 它们参与了神经胶质细胞的肿瘤发生过程。我们的 假设是：1)胶质瘤细胞的恶性表型依赖于 PDGF型信号通路对原癌基因c-myc的激活作用 (c-sis/PDGF-β和干细胞因子)，2)PBR、a的表达 胶质瘤细胞的推定标记物，有助于恶性 细胞的行为，以及3)PBR可以通过这些行为来表达 原癌基因。 恶性神经胶质瘤仍然是一种毁灭性的疾病，它只对 暂时转向目前的治疗方法。因为有选择性地表达 恶性神经胶质瘤的PBR(Broaddus和Bennett，1990)，这种结合 SITE是选择性成像肿瘤细胞和靶向的候选者 对他们进行治疗。该项目的具体目标包括以下计划 演示该成分在神经胶质瘤细胞中的定位 原位杂交，这项技术的精确度比 迄今已用于组织学研究PBR在肿瘤中的表达 细胞。 围绕恶变机制，开展 研究表明c-myc和PBR表达的变化与 胶质瘤细胞恶性特性的改变。最后，我们建议 用反义基因序列证明恶性肿瘤的依赖性 C-myc可能是自分泌生长因子系统表达的表型 (C-sis和SCF)和PBR。这些研究将提供更好的理解 关于胶质细胞恶性进展的机制， 并有助于确定PBR作为成像目标的潜在用途 并指导细胞毒策略。成功地使用反义技术 寡核苷酸序列逆转神经胶质瘤细胞增殖 对基因治疗策略也有潜在的适用性。

The purpose of the proposed project is to study the mechanisms of malignant behavior in glioma cells. We will study expression of the peripheral benzodiazepine receptor (PBR) and activation of proto-oncogenes which have been implicated in the process of glial cell oncogenesis. Our hypotheses are: 1) the malignant phenotype in glioma cells is dependent on activation of the proto-oncogene c-myc by PDGF-type signalling pathways (c-sis/PDGF-beta and Stem Cell Factor), 2) expression of the PBR, a putative marker for glial tumor cells, contributes to the malignant behavior of the cells, and 3) PBR may be expressed by the actions of these proto-oncogenes. Malignant glial tumors remain a devastating disease which responds only transiently to current therapies. Because of the selective expression of PBR by malignant glial tumors (Broaddus and Bennett, 1990), this binding site is a candidate for selectively imaging tumor cells and targeting therapies at them. The specific aims of this project encompass plans to demonstrate localization of this component to glial tumor cells using in situ hybridization, a technique which allows much higher precision than has been used thus far in histological studies of PBR expression by tumor cells. Focussing on mechanisms of malignant transformation, we will carry out studies to show an association of changes in c-myc and PBR expression with alteration of malignant characteristics glioma cells. Finally, we propose to use antisense gene sequences to demonstrate dependence of malignant phenotype on expression of c-myc, putative autocrine growth factor systems (c-sis and SCF) and PBR. These studies will provide better understanding of the mechanisms involved in the malignant progression of glial cells, and help define the potential utility of the PBR as a target for imaging and directing cytotoxic strategies. Successful use of antisense oligonucleotide sequences to reverse glial tumor cell proliferation will also have potential applicability to gene therapy strategies.