FAK and Pky2 in Determination of Glioblastoma Phenotype

FAK 和 Pky2 在胶质母细胞瘤表型测定中的应用

• 批准号: 7233703
• 负责人: JOSEPH C LOFTUS
• 金额: $ 26.1万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-25 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7233703
• 关键词: 3-Dimensional; Adhesives; Apoptosis; Behavior; Brain; Cell Proliferation; Cells; Cessation of life; Clinical; Development; Equilibrium; Excision; Extracellular Matrix; Focal Adhesion Kinase 1; Gene Expression Profiling; Genes; Glioblastoma; Glioma; Growth; Human; Integrins; Invaded; Invasive; Link; Malignant - descriptor; Malignant Glioma; Mediating; Molecular; Outcome; PTK2 gene; Phenotype; Phosphotransferases; Play; Primary Neoplasm; Process; Radiation; Regulation; Relative (related person); Resistance; Role; Severity of illness; Signal Pathway; Signal Transduction; Site; Tissue-Specific Gene Expression; Tumor Cell Invasion; base; brain tissue; cancer cell; cell motility; chemotherapeutic agent; improved; in vivo; insight; migration; novel therapeutics; outcome forecast; tumor

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.

描述（由申请人提供）：恶性神经胶质瘤细胞侵入周围正常脑组织会导致临床预后不良。这些细胞的迁移阻碍了有效的肿瘤切除，降低了放射治疗的功效，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明确，但与细胞外基质（ECM）的粘附相互作用在此过程中发挥着重要作用。参与细胞增殖、迁移和存活/死亡的整合素调节信号通路的相对激活状态可能是肿瘤侵袭中恶性细胞侵袭性的重要决定因素。我们假设粘着斑激酶 FAK 和 Pyk2 在侵袭性神经胶质瘤的恶性行为中充当重要的信号传导效应器。此外，我们假设 FAK 和 Pyk2 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。该提案的目的是明确 FAK 和 Pyk2 在恶性胶质瘤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 Pyk2 对胶质母细胞瘤细胞迁移或增殖的不同作用所需的特定功能域来确定 FAK 和 Pyk2 在调节胶质母细胞瘤迁移和增殖中的不同作用的基础。其次，我们将确定 FAK 和 Pyk2 的特异性抑制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 Pyk2 和 FAK 功能对体内 3 维脑微环境中胶质母细胞瘤侵袭行为的作用，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，这些研究将为效应激酶 FAK 和 Pyk2 影响胶质母细胞瘤迁移和增殖的细胞信号网络提供更多的见解。由于增殖和迁移是这种疾病严重程度不可或缺的一部分，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以改善临床结果。