TRANSFORMATION DEPENDENT GENE EXPRESSION IN GLIOMA CELLS

该项目的目的是研究 神经胶质瘤细胞的恶性行为。我们将研究 外周苯二氮卓受体与原癌基因激活 其与神经胶质细胞肿瘤发生过程有关。我们 假设是：1）胶质瘤细胞中的恶性表型依赖于 通过PDGF型信号通路激活原癌基因c-myc （c-sis/PDGF-β和干细胞因子），2）PBR的表达， 神经胶质瘤细胞的假定标志物，有助于恶性肿瘤的发生。 细胞的行为，以及3）PBR可以通过这些细胞的行为来表达。 原癌基因 恶性神经胶质瘤仍然是一种毁灭性的疾病， 目前的治疗方法。由于选择性表达 恶性神经胶质瘤的PBR（布罗德斯和班尼特，1990），这种结合 位点是选择性成像肿瘤细胞和靶向 治疗他们。该项目的具体目标包括计划， 证明该成分定位于神经胶质肿瘤细胞， 原位杂交技术，一种比原位杂交技术精确得多的技术， 迄今为止，已用于肿瘤PBR表达的组织学研究， 细胞 针对恶性转化的机制，我们将开展 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。最后提出 使用反义基因序列来证明恶性肿瘤的依赖性， 表型对c-myc表达的影响，假定的自分泌生长因子系统 （c-sis和SCF）和PBR。这些研究将提供更好的理解 神经胶质细胞恶性进展的机制， 并帮助确定PBR作为成像靶点的潜在效用 并指导细胞毒策略。成功使用反义 逆转神经胶质肿瘤细胞增殖的寡核苷酸序列将 还具有基因治疗策略的潜在适用性。

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.