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：
7684254
负责人：
ISA M HUSSAINI
金额：
$ 22.73万
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/7684254
关键词：
Adjuvant Therapy Affect Animal Model Applications Grants Astrocytoma Brain Cell Line Cell Proliferation Cells Consensus Sequence Data Diagnosis Distant Excision Expert Opinion Gelatinase B Genes Glioblastoma Growth Human Image Immunohistochemistry In Vitro Invaded Isoenzymes Magnetic Resonance Imaging Malignant - descriptor Matrix Metalloproteinases Mediating Migration Assay Molecular NF-kappa B NOD/SCID mouse Oncogenes Operative Surgical Procedures Pathway interactions Patients Pattern Peptide Hydrolases Phosphotransferases Play Primary Brain Neoplasms Process Promoter Regions 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 public health relevance 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（由申请人提供）：恶性星形肿瘤患者的预后很差。星形胶质细胞瘤的能力既可以入侵相邻的大脑部位并迁移到远处的脑部位，从而排除了治愈性手术切除的能力。在设计显着影响长期生存的辅助疗法方面，几乎没有取得进展。为了制定更新颖的治疗策略，必须更好地了解如何控制这些肿瘤的侵入性生长。我们的动物模型和体外结果表明，即使PKC-ETA表达增加了有丝分裂的反应，但胶质母细胞瘤细胞的侵入性较小。我们的工作假设是：PKC-ETA的表达和激活减少星形肿瘤的侵袭。提出了三个目的来检验假设（i），以确定控制星形肿瘤细胞中PKC-ETA表达的因素（II），以确定PKC-ETA介导的胶质母细胞瘤侵入体外和（III）中PKC-ETA介导的降低的作用和机制，以评估GbM Invasige n of sc-Eta在XENORD中的作用。免疫组织化学，组织切片迁移和磁共振成像（MRI）。公共卫生相关性：被称为胶质母细胞瘤的星形细胞瘤的恶性形式是最常见的原发性脑肿瘤。该肿瘤对化学疗法和放射线具有抗性。多种因素和途径与多形胶质母细胞瘤的形成和进展有关。该研究项目已将新型的PKC同工酶（PKC-ETA）确定为一种分子开关，当在GBM中表达时，细胞会变得高度增殖且侵入性较小。相反，当这种激酶不存在时，GBM细胞会变得高度侵入性。此外，我们已经确定了PKC-ETA的推定下游靶标（MMP-9）和转录因子（NF-KB），该目标可能解释了控制GBM侵袭GBM在体外和体内的众多机制之一。了解这些基因在GBM侵袭中的功能作用可能会提供一个范式，从而可以管理这种致命的肿瘤。