Dissecting Glioma Genesis through a Glial-Specific Mouse Model

通过神经胶质特异性小鼠模型剖析神经胶质瘤的起源

基本信息

批准号：
8518250
负责人：
GREGORY Neal FULLER
金额：
$ 23.77万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518250
关键词：
Ablation Alleles Angiogenesis Pathway Cell Survival Data Development Drug Targeting Event Exhibits Family member Funding Genomics Genotype Glioblastoma Glioma Gliomagenesis Goals Histopathology Human Injection of therapeutic agent Investigation Lead Maintenance Malignant neoplasm of prostate Mediating Modeling Molecular Mouse Strains Mus Mutate Mutation Oligodendroglioma-Astrocytoma Oncogenes Oncogenic PTEN Gene Inactivation PTEN gene Pathway interactions Phenotype Proto-Oncogene Proteins c-sis Publishing Role Signal Pathway System Testing Tetanus Helper Peptide The Cancer Genome Atlas Therapeutic Time Transgenic Mice Tumor Suppressor Genes Vascular Endothelial Growth Factors angiogenesis human IGFBP2 protein in vivo inhibitor/antagonist insight member mouse model nestin protein novel oligodendroglioma public health relevance research study therapeutic target tumor vector

项目摘要

DESCRIPTION (provided by applicant): The major goal of the last funding period was to use a glial-specific transgenic mouse model, the RCAS-tv-a system, to functionally determine the oncogenic role of insulin-like growth factor binding protein 2 (IGFBP2), which was identified from our genomic profiling studies as a marker for high-grade gliomas. We have achieved this goal, and for the first time discovered that IGFBP2 is a novel oncogene that, when combined with K-ras or platelet-derived growth factor beta (PDGFB), leads to the development and progression of two major types of glioma (astrocytoma and oligodendroglioma) (Dunlap et al., 2007). Our in vivo and ex vivo studies revealed that IGFBP2 activates the Akt pathway, and that pharmacological inhibition of Akt blocks IGFBP2-mediated cell viability. This finding is supported by recent data from Charles Sawyers' group showing that IGFBP2 over-expression in glioblastoma and prostate cancer is associated with PTEN mutation and PI3K/Akt activation (Mehrian-Shai et al., 2007). Our recent studies have shown that IGFBP2 activates the expression of VEGF and promotes angiogenesis. In this R01 renewal, we will test our hypothesis that IGFBP2 is important for glioma maintenance and that IGFBP2, in combination with the loss of PTEN, most efficiently activates the Akt and angiogenesis pathways, and results in progression of gliomas to glioblastoma. We will use our established RCAS system together with a Tet-inducible RCAS system for these studies. Our specific aims are the following. Specific aim 1. To determine the role of IGFBP2 over-expression in the maintenance of high grade gliomas. Specific aim 2. To determine which of the three Akt family members (Akt1, Akt2, and Akt3) is most important for glioma development and progression. Specific aim 3. To determine the cooperation of oncogene over-expression with PTEN inactivation to promote GBM. Specific aim 4. Effect of IGFBP2 expression on Akt and VEGF pathway therapeutics. PUBLIC HEALTH RELEVANCE: The significance of this study is to understand the mechanism and potentially key signaling pathways (Akt and VEGF) of a newly recognized oncogene of glioma, insulin-like growth factor binding protein 2 (IGFBP2) in maintenance of high-grade glioma and the crosstalk between IGFBP2 signaling pathway and inactivation of PTEN tumor suppressor gene. This in-depth understanding will provide insight in the development of targeted therapeutics for high-grade gliomas.

描述（由申请人提供）：上次融资期的主要目标是使用神经胶质特异性的转基因小鼠模型RCAS-TV-A系统，在功能上确定胰岛素样生长因子结合蛋白2的致癌作用（ IGFBP2），这是从我们的基因组分析研究中确定为高级神经胶质瘤的标志物。我们已经实现了这一目标，并且第一次发现IGFBP2是一种新颖的癌基因，当与K-RAS或血小板衍生的生长因子β（PDGFB）结合使用时，会导致两种主要类型的胶质瘤（星形胶质细胞瘤和少突可瘤瘤）（Dunlap等，2007）。我们的体内和离体研究表明，IGFBP2激活了AKT途径，并且药理抑制AKT阻断了IGFBP2介导的细胞活力。 Charles Sawyers组的最新数据支持了这一发现，表明胶质母细胞瘤和前列腺癌中的IGFBP2过表达与PTEN突变和PI3K/AKT激活有关（Mehrian-Shai等，2007）。我们最近的研究表明，IGFBP2激活VEGF的表达并促进血管生成。在此R01更新中，我们将测试我们的假设，即IGFBP2对于胶质瘤维持很重要，并且IGFBP2与PTEN的丧失结合使用，最有效地激活了Akt和血管生成途径，并导致胶质瘤向神经胶质细胞瘤的进展。我们将使用已建立的RCAS系统以及TET诱导的RCAS系统进行这些研究。我们的具体目标是以下内容。具体目标1。确定IGFBP2过表达在维持高级神经胶质瘤中的作用。具体目的2。确定三个AKT家族成员（AKT1，AKT2和AKT3）中的哪个对于神经胶质瘤的发展和进展最为重要。具体目的3。确定癌基因过表达与PTEN失活以促进GBM的合作。具体目标4。iGFBP2表达对AKT和VEGF途径疗法的影响。公共卫生相关性：这项研究的重要性是了解新认识的神经胶质瘤，胰岛素样生长因子结合蛋白2（IGFBP2）的机制和潜在的关键信号通路（AKT和VEGF）以及IGFBP2信号通路和PTEN肿瘤抑制基因失活之间的串扰。这种深入的理解将为高级神经胶质瘤的有针对性治疗剂的发展提供洞察力。