Receptor Tyrosine Kinase/PTEN Interactions in Gliomas

胶质母细胞瘤是极具侵袭性和致命性的脑肿瘤。从低级别胶质瘤到胶质母细胞瘤的进展通常与肿瘤抑制磷酸酶PTEN的功能丧失以及致癌生长因子途径如SF/HGF及其酪氨酸激酶受体c-met的过表达相关。虽然PTEN和SF/HGF：c-met在胶质瘤中的致瘤性和恶性性质已有很好的文献记载，但知之甚少 关于它们如何共同调节各种分子、细胞和恶性参数。由于有证据表明，它们之间的直接相互作用的水平上的细胞信号，知识的相互依赖性是非常重要的了解的机制，神经胶质瘤恶性肿瘤的基础和设计的治疗against it. This应用程序提出研究如何PTEN和c-met酪氨酸激酶依赖的途径共同调节细胞周期，细胞凋亡，细胞信号和基因转录在人脑胶质瘤。它还将测试神经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、凋亡和相关的细胞信号传导和转录事件。目的#2将确定体内结合PTEN重建和受体酪氨酸激酶/生长因子抑制是否具有治疗优势。目的#3将确定PTEN和受体酪氨酸激酶途径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。这些研究将提供一个更好的了解酪氨酸激酶/癌基因和磷酸酶/肿瘤抑制因子之间的相互作用机制在胶质瘤的发生和恶性。这些研究将确定新的基因， 由PTEN和致癌受体酪氨酸激酶反向调节。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，并将导致识别新的候选靶点，以获得更有效的治疗方法。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.