Receptor Tyrosine Kinase/PTEN Interactions in Gliomas

胶质母细胞瘤是一种极具侵袭性和致命性的脑瘤。从低级别胶质瘤到胶质母细胞瘤的进展通常与肿瘤抑制基因磷酸酶PTEN的功能丧失以及肿瘤生长因子通路如SF/HGF及其酪氨酸激酶受体c-met的过度表达有关。尽管PTEN和SF/HGF：C-MET在神经胶质瘤中的致瘤和恶性特性已有很好的文献记载，但鲜为人知 关于它们如何共同调节各种分子、细胞和恶性肿瘤参数。由于有证据表明它们在细胞信号水平上直接相互作用，了解它们之间的相互依赖关系对于理解胶质瘤恶性肿瘤的发病机制和设计治疗方法具有重要意义。这项应用旨在研究PTEN和c-MET酪氨酸激酶依赖的通路如何共同调节人脑胶质瘤的细胞周期、细胞凋亡、细胞信号和基因转录。它还将测试胶质瘤基因的新策略 治疗和放疗/化疗。目的#1将确定PTEN和SF/HGF：C-MET如何共同调节细胞周期、细胞凋亡以及相关的细胞信号和转录事件。目的#2将确定体内PTEN重组和受体酪氨酸激酶/生长因子抑制联合应用是否具有治疗优势。目的#3将确定PTEN和受体酪氨酸激酶通路如何共同调节胶质瘤细胞和人类组织微阵列中肿瘤相关基因的表达。这些研究将有助于更好地理解酪氨酸激酶/癌基因和磷酸酶/肿瘤抑制因子在胶质瘤发生和恶性过程中的相互作用机制。这些研究将识别出新的基因 受PTEN和致癌受体酪氨酸激酶的反向调节。分析这些基因的表达变化将有助于了解它们在PTEN/生长因子介导的恶性肿瘤中的作用，并将有助于识别更有效的治疗新的候选靶点。拟议的研究还将开发多基因靶向策略 神经胶质瘤治疗。

Glioblastomas are extremely aggressive and lethal brain tumors. Progression from low grade glioma to glioblastoma is often associated with loss of function of the tumor suppressor phosphatase PTEN as well as overexpression of oncogenic growth factor pathways such as SF/HGF and its tyrosine kinase receptor c-met. Although the tumorigenic and malignant properties of PTEN and SF/HGF:c-met in gliomas are well documented, little is known on how they co-regulate various molecular, cellular and malignancy parameters. Since there is evidence of their direct interaction at the level of cell signaling, knowledge of their interdependencies is of importance for understanding the mechanisms that underlie glioma malignancy and for the design of cures against it. This application proposes to study how PTEN and c-met tyrosine kinase-dependent pathways co-regulate cell cycle, apoptosis, cell signaling and gene transcritiption in human gliomas. It will also test new strategies for glioma gene therapy and radio-/chemotherapy. Aim # 1 will determine how PTEN and SF/HGF:c-met co-regulate cell cycle, apoptosis and associated cell signaling and transcriptional events. Aim # 2 will determine if combining PTEN reconstitution and receptor tyrosine kinase/growth factor inhibition in vivo has therapeutic advantages. Aim #3 will determine how PTEN and receptor tyrosine kinase pathways co-regulate the expression of neoplasia-related genes in glioma cells and human tissue microarrays. These studies will provide a better understanding of the mechanistic interactions between tyrosine kinases/oncogenes and phosphatases/tumor suppressors in glioma genesis and malignancy. The studies will identify new genes that are inversely regulated by PTEN and oncogenic receptor tyrosine kinases. Analyzing the expression changes of these genes i will help understand their role in PTEN/growth factor-mediated malignancy and will lead to the identification of new candidate targets for more effective therapies. The proposed studies will also develop multi-gene targeting strategies for glioma therapy.