REGULATION OF GBM INVASIVE GROWTH BY PROTEIN KINASE C-ETA

蛋白激酶 C-ETA 对 GBM 侵袭性生长的调节

基本信息

批准号：
7524755
负责人：
ISA M HUSSAINI
金额：
$ 21.39万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7524755
关键词：
Adjuvant Therapy Affect Animal Model Applications Grants Astrocytoma Brain Brain Neoplasms Cell Line Cell Proliferation Cells Consensus Sequence Data Depth Diagnosis Distant Endopeptidases Excision Expert Opinion Gelatinase B Genes Glioblastoma Growth Human Image Immunohistochemistry In Vitro Invaded Invasive Isoenzymes Magnetic Resonance Imaging Malignant - descriptor Matrix Metalloproteinases Mediating Migration Assay Molecular NF-kappa B Oncogenes Operative Surgical Procedures Pathway interactions Patients Pattern Peptide Hydrolases Phosphotransferases Play Process Promoter Regions Public Health Radiation Regulation Research Project Grants Resistance Role SCID Mice Sirolimus Site Slice Subfamily lentivirinae Testing Tissues Tumor Cell Invasion Urokinase Work Xenograft procedure chemotherapy design implantation in vivo migration mouse model neoplastic cell neuro-oncology novel novel therapeutics outcome forecast promoter protein kinase C eta response small hairpin RNA therapeutic target transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The prognosis for patients with malignant astrocytic tumors is poor. The capacity of astrocytomas both to invade adjacent brain sites and to migrate into distant ones precludes curative surgical resection; and little progress has been made in designing adjuvant therapies that significantly affect long-term survival. In order to formulate more novel therapeutic strategies, it is essential to have a better understanding of how the invasive growth of these tumors is controlled. Our animal model and in vitro results suggest that even though PKC-eta expression increases mitogenic response, the glioblastoma cells are less invasive. Our working hypothesis is: Expression and activation of PKC-eta decrease astrocytic tumor invasion. Three aims are proposed to test the hypothesis (I) To determine the factors controlling the expression of PKC-eta in astrocytic tumor cells (II) To determine the role and mechanism of PKC-eta-mediated decrease in glioblastoma invasion in vitro and (III) To assess the role of PKC-eta expression on GBM invasive growth in a xenograft GBM NOD- SCID mouse model using immunohistochemistry, tissue slice migration and magnetic resonance imaging (MRI). PUBLIC HEALTH RELEVANCE: The malignant form of astrocytoma known as glioblastoma multiforme is most commonly diagnosed primary brain tumor. This tumor is resistant to chemotherapy and radiation. There are multiple factors and pathways that are involved in the formation and progression of glioblastoma multiforme. This research project has identified a novel PKC isozyme (PKC-eta) as a molecular switch that when expressed in GBM, cells become highly proliferative and less invasive. In contrast, when this kinase is absent the GBM cells become highly invasive. Furthermore, we have identified a putative downstream target (MMP-9) of PKC-eta and a transcription factor (NF-kB) that may explain one of the many mechanisms for controlling GBM invasion both in vitro and in vivo. Understanding the functional roles of these genes in GBM invasion may provide a paradigm whereby this deadly tumor may be managed.

描述（申请人提供）：恶性星形细胞肿瘤患者的预后较差。星形细胞瘤既能侵入邻近的大脑部位，又能迁移到远处的大脑部位，因此无法进行根治性手术切除；在设计显着影响长期生存的辅助疗法方面进展甚微。为了制定更新颖的治疗策略，有必要更好地了解如何控制这些肿瘤的侵袭性生长。我们的动物模型和体外结果表明，尽管 PKC-eta 表达增加有丝分裂反应，但胶质母细胞瘤细胞的侵袭性较小。我们的工作假设是：PKC-eta 的表达和激活减少星形细胞肿瘤的侵袭。提出了三个目标来检验该假设（I）确定控制星形细胞肿瘤细胞中 PKC-eta 表达的因素（II）确定 PKC-eta 介导的体外胶质母细胞瘤侵袭减少的作用和机制以及（III） ) 使用免疫组织化学、组织切片迁移和磁共振成像 (MRI) 评估 PKC-eta 表达对异种移植 GBM NOD-SCID 小鼠模型中 GBM 侵袭性生长的作用。公共卫生相关性：恶性星形细胞瘤（称为多形性胶质母细胞瘤）是最常诊断的原发性脑肿瘤。这种肿瘤对化疗和放疗具有抵抗力。多形性胶质母细胞瘤的形成和进展涉及多种因素和途径。该研究项目确定了一种新型 PKC 同工酶 (PKC-eta) 作为分子开关，当在 GBM 中表达时，细胞变得高度增殖且侵袭性较小。相反，当这种激酶缺失时，GBM 细胞就会变得高度侵袭性。此外，我们还确定了 PKC-eta 的假定下游靶标 (MMP-9) 和转录因子 (NF-kB)，它们可以解释体外和体内控制 GBM 侵袭的多种机制之一。了解这些基因在 GBM 侵袭中的功能作用可能会提供一个范例，从而可以控制这种致命的肿瘤。