FAK and Pky2 in Determination of Glioblastoma Phenotype

描述（由申请人提供）：恶性胶质瘤细胞侵入周围正常脑组织显著导致临床预后不良。这些细胞迁移的承诺排除了有效的肿瘤切除术，降低了放射治疗的疗效，并增加了对化疗药物的耐药性。调节胶质瘤从原发肿瘤部位迁移的分子机制尚未确定，但与细胞外基质（ECM）的粘附相互作用在这一过程中起着重要作用。参与细胞增殖、迁移和存活/死亡的整合素调节的信号通路的相对活化状态可能是恶性细胞在肿瘤侵袭中的侵袭性的重要决定因素。我们假设粘着斑激酶FAK和Pyk 2在侵袭性胶质瘤的恶性行为中起重要的信号效应器的作用。此外，我们假设FAK和Pyk 2活性之间的动态平衡及其差异调节是增殖或迁移表型的时间表现的决定因素。本研究的目的是明确FAK和Pyk 2在恶性胶质瘤的异常生长和侵袭中的具体作用。拟议的研究将首先通过确定FAK和Pyk 2对胶质母细胞瘤细胞迁移或增殖的差异效应所需的特定功能结构域，来确定FAK和Pyk 2在胶质母细胞瘤迁移和增殖调节中的差异效应的基础。其次，我们将确定特异性抑制FAK和Pyk 2对胶质母细胞瘤增殖和迁移的影响，并确定这些表型行为是否呈负相关或可以独立调节。最后，我们将研究Pyk 2和FAK功能对成胶质细胞瘤在体内三维脑微环境中的侵袭行为的作用，并使用差异基因表达谱来识别与迁移/增殖/凋亡相关的基因组的改变。总的来说，这些研究将提供额外的洞察细胞信号网络的效应激酶FAK和Pyk 2的功能，以影响胶质母细胞瘤的迁移和增殖。由于增殖和迁移都是这种疾病严重程度的组成部分，因此需要更深入地了解调节这些不同细胞行为的分子机制，以开发新的治疗策略来改善临床结果。

DESCRIPTION (provided by applicant): Invasion of malignant gliomas cells into surrounding normal brain tissue contributes significantly to poor clinical prognosis. The commitment of these cells to migration precludes effective tumor resection, reduces the efficacy of radiation treatment, and increases resistance to chemotherapeutic agents. The molecular mechanisms that regulate the migration of gliomas from primary tumor sites have not been defined but adhesive interactions with extracellular matrix (ECM) play an important role in this process. The relative activation states of integrin regulated signaling pathways involved in cell proliferation, migration, and survival/death are likely to be important determinants of the aggressiveness of malignant cells in tumor invasion. We hypothesize that the focal adhesion kinases FAK and Pyk2 function as important signaling effectors in the malignant behavior of invasive gliomas. Furthermore, we hypothesize that the dynamic balance between FAK and Pyk2 activity and their differential regulation are determining factors in the temporal manifestation of proliferative or migrational phenotypes. The objective of this proposal is to define the specific roles of FAK and Pyk2 in the abnormal growth and invasion of malignant gliomas. The proposed studies will first define the basis for the differential effects of FAK and Pyk2 in regulation of glioblastoma migration and proliferation by identifying specific functional domains of FAK and Pyk2 that are required for their differential effects on glioblastoma cell migration or proliferation. Secondly, we will determine the effect of specific inhibition of FAK and Pyk2 on glioblastoma proliferation and migration and determine whether these phenotypic behaviors are inversely linked or can be modulated independently. Finally, we will investigate the role of Pyk2 and FAK function on the invasive behavior of glioblastomas in the 3-dimensional brain microenvironment in vivo and use differential gene expression profiling to identify alterations in sets of genes associated with migration/proliferation/apoptosis. Overall, these studies will provide additional insight into the cellular signaling networks by which the effector kinases FAK and Pyk2 function to influence glioblastoma migration and proliferation. Since both proliferation and migration are integral to the severity of this disease, greater insights into the molecular mechanisms that regulate these distinct cellular behaviors are required for the development of novel therapeutic strategies to improve clinical outcomes.