Genetic Mouse Models of Glioma

神经胶质瘤的遗传小鼠模型

• 批准号: 8010613
• 负责人: Luis Fernando Parada
• 金额: $ 39.03万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010613
• 关键词: Ablation; Address; Adult; Alleles; Anaplastic astrocytoma; Appearance; Astrocytoma; Attention; Brain Neoplasms; Brain region; Cell surface; Cells; Central Nervous System Neoplasms; Complement; Coupled; Data; Development; Diagnostic Neoplasm Staging; Differentiation and Growth; Drug Delivery Systems; Event; Gene Expression; Genes; Genetic; Genomics; Genotype; Glioblastoma; Glioma; Growth; Health; Histologic; Human; Investigation; Knock-out; Laboratories; Loss of Heterozygosity; Malignant Neoplasms; Methods; MicroRNAs; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Mouse Strains; Mus; Mutant Strains Mice; Mutate; Mutation; NF1 gene; NF1 tumor suppressor; Nature; Neoplasm Metastasis; Nervous system structure; Neural Crest; Neurofibromatoses; Neuroglia; Nude Mice; Oncogenic; PTEN gene; Pathway interactions; Patients; Penetrance; Penetrance analysis; Peripheral Nervous System Neoplasms; Physiological; Platelet-Derived Growth Factor Receptor; Process; Property; Protein p53; RNA Interference; Radial; Reporting; Research; Research Design; Risk; Role; Signal Pathway; Stem cells; Tamoxifen; Techniques; Testing; The Cancer Genome Atlas; Therapeutic; Thymidine Kinase; Tissues; Transgenic Mice; Transplantation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Tumor stage; Work; adult stem cell; base; cancer stem cell; cell type; clinically relevant; design; epidermal growth factor receptor VIII; follow-up; insight; interest; mouse model; mutant; neonate; neoplastic cell; nerve stem cell; nestin protein; neurodevelopment; neurofibroma; neuropathology; novel; outcome forecast; overexpression; progenitor; promoter; relating to nervous system; research study; stem; stem cell niche; stem cell population; subventricular zone; therapy development; tool; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Malignant astrocytomas are brain tumors that are locally infiltrative and incurable, with poor prognosis for the patient. Despite profound therapeutic implications, the identity of the cell(s) of origin of these tumors has not been rigorously determined. In addition, glioblastoma multiforme, the most prevalent and deadly form of brain tumor, can either progress from lower grade astrocytic gliomas or arise de novo, the mechanisms by which are not well understood. We previously reported mouse models based on conditional inactivation of human astrocytoma-relevant tumor suppressors p53, Nf1, and Pten, wherein through somatic loss of heterozygosity, mutant mice develop tumors that histologically and molecularly resemble human astrocytomas with 100% penetrance. In the present application, we propose experiments designed to investigate the cell(s) of tumor origin and to extend our analyses of tumorigenesis in these mouse models. To this end, Specific Aim 1 rigorously tests our hypothesis that gliomas originate in stem/progenitor cells. Our research design utilizes genetic and stereotactic methods to mutate the tumor suppressor genes specifically in the stem cell niche. We will also use a genetic method to ablate these neural stem cells in our tumor models and then analyze the effect on tumor formation. Specific Aim 2 will exploit our ability to culture fresh tumor tissue as self-renewable neurospheres to further characterize our Nf1;p53;Pten "de novo" glioma mouse model. We will evaluate their growth and differentiation properties, as well as their tumorigenic potential via transplantation techniques. Additionally, using a stem cell-specific GFP transgenic mouse, we will analyze the expression of candidate cell surface markers with the aim of identifying "signature markers" that will allow us to prospectively isolate the cancer stem cells. Specific Aim 3 will employ microarray analyses to identify the gene expression profiles that correlate with de novo vs. progressive glioma, using neurospheres derived from Nf1;p53;Pten and Nf1;p53 tumors, respectively. We also propose to analyze tissue from pre-symptomatic mice in order to gain insight into the early molecular events of tumor initiation. Potentially interesting genes will be functionally pursued using RNAi and overexpression techniques. As microRNAs have recently been implicated in glioma, we will also use microarray analysis to identify microRNAs that are differentially regulated in our tumor models and also investigate the role of candidate microRNAs in glioma. Our fully penetrant glioma mouse models are clinically relevant and powerful tools for identifying and functionally characterizing novel genes and pathways that may be therapeutically tractable in human glioma. PUBLIC HEALTH RELEVANCE: Malignant astrocytomas are the most common type of brain tumors that occur in adults and due to their infiltrative and aggressive nature, are virtually incurable. The focus of our research is to use mouse brain tumor models to identify and analyze genes that are involved in brain tumor initiation and progression. The hope is that by identifying these genes, we might begin to find suitable drug targets and develop therapies that would eliminate or inhibit the growth of these devastating tumors.

描述（由申请人提供）：恶性星形胶质细胞瘤是局部渗透性且无法治愈的脑肿瘤，患者的预后不佳。尽管具有深远的治疗意义，但这些肿瘤起源细胞的身份尚未得到严格确定。此外，胶质母细胞瘤多形是脑肿瘤的最普遍，最致命的形式，可以从低级星形胶质细胞神经胶质瘤或从头开始，而从头开始，这种机制尚不清楚。我们先前报道了小鼠模型基于人类星形细胞瘤肿瘤抑制剂p53，NF1和PTEN的条件失活，其中通过杂合性的体细胞丧失，突变小鼠会形成组织学和分子上的肿瘤，与人类星形瘤具有100％渗透率。在本应用中，我们提出的实验旨在研究肿瘤起源的细胞，并在这些小鼠模型中扩展肿瘤发生分析。为此，特定的目标1严格检验了我们的假设，即神经胶质瘤起源于茎/祖细胞。我们的研究设计利用遗传学和立体定向方法突变在干细胞小裂中的肿瘤抑制基因。我们还将使用遗传方法在肿瘤模型中消除这些神经干细胞，然后分析对肿瘤形成的影响。特定的目标2将利用我们培养新鲜肿瘤组织的能力，作为可自我再生神经球，进一步表征我们的NF1； p53; pten“ de de de de de Nop” Glioma小鼠模型。我们将通过移植技术评估它们的生长和分化特性及其致密性潜力。此外，使用干细胞特异性的GFP转基因小鼠，我们将分析候选细胞表面标记的表达，目的是识别“签名标记”，这将使我们能够前瞻性地分离癌症干细胞。具体目标3将采用微阵列分析来鉴定与从头开始与促进胶质瘤相关的基因表达谱，分别使用NF1; p53； pten和nf1; p53肿瘤得出的神经球。我们还建议分析来自症状前小鼠的组织，以深入了解肿瘤启动的早期分子事件。潜在有趣的基因将使用RNAi和过表达技术在功能上追求。由于最近与神经胶质瘤有关的microRNA，我们还将使用微阵列分析来鉴定在我们的肿瘤模型中受到差异调节的microRNA，并研究候选microRNA在神经胶质瘤中的作用。我们完全渗透性神经胶质瘤小鼠模型是临床相关且强大的工具，可在人神经胶质瘤中识别和功能表征新型基因和途径。公共卫生相关性：恶性星形胶质细胞瘤是成年人中最常见的脑肿瘤类型，并且由于其渗透性和侵略性，实际上是无法治愈的。我们研究的重点是使用小鼠脑肿瘤模型来识别和分析与脑肿瘤启动和进展有关的基因。希望通过鉴定这些基因，我们可能会开始找到合适的药物靶标，并开发出消除或抑制这些毁灭性肿瘤生长的疗法。