FAK and Pky2 in Determination of Glioblstoma Phenotype

FAK 和 Pky2 在胶质母细胞瘤表型测定中的应用

• 批准号: 7115946
• 负责人: JOSEPH C LOFTUS
• 金额: $ 26.91万
• 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/7115946
• 关键词: cell adhesion; cell migration; cell proliferation; extracellular matrix; focal adhesion kinase; glioblastoma multiforme; human tissue; laboratory mouse; laboratory rat; neoplasm /cancer invasiveness; neoplasm /cancer transplantation; neoplastic growth; xenotransplantation

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）：侵袭恶性神经胶质瘤细胞周围正常的脑组织，对临床预后不良显着贡献。这些细胞对迁移的承诺排除了有效的肿瘤切除，降低了放射治疗的功效，并增加了对化学治疗剂的耐药性。尚未定义调节神经胶质瘤从原发性肿瘤部位迁移的分子机制，但与细胞外基质（ECM）的粘合剂相互作用在此过程中起着重要作用。整合素调节的信号通路的相对激活状态与细胞增殖，迁移和生存/死亡有关，可能是恶性细胞在肿瘤侵袭中侵袭性的重要决定因素。我们假设局灶性激酶FAK和PYK2在侵入性神经胶质瘤的恶性行为中起重要信号传导效应子。此外，我们假设FAK和PYK2活性及其差异调节之间的动态平衡是在增殖或迁移表型的时间表现中确定因素。该提案的目的是定义FAK和PYK2在异常生长和侵袭恶性神经胶质瘤中的特定作用。拟议的研究将首先定义FAK和PYK2在调节胶质母细胞瘤迁移和增殖中的差异效应的基础，这是通过鉴定FAK和PYK2的特定功能域对胶质母细胞瘤细胞迁移或增殖所必需的特定功能域的基础。其次，我们将确定FAK和PYK2对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功能在体内3维脑微环境中胶质母细胞瘤的侵入性行为的作用，并使用差异基因表达分析来识别与迁移/增殖/增殖/凋亡相关的基因集的变化。总体而言，这些研究将提供对细胞信号网络的更多见解，效应激酶FAK和PYK2功能影响胶质母细胞瘤迁移和增殖。由于增殖和迁移都是该疾病严重程度不可或缺的一部分，因此对调节这些不同细胞行为的分子机制有更多的见解是发展新型治疗策略以改善临床结果的必要的。