Genetic Dissection of Glioblastoma: Cell of Origin

胶质母细胞瘤的基因剖析：起源细胞

基本信息

批准号：
8499438
负责人：
Robert M. Bachoo
金额：
$ 32.99万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499438
关键词：
Address Adult Astrocytes Basic Science Behavior Biological Biological Process Biology Brain Cancer Genome Anatomy Project Cell Differentiation process Cell Line Cell Lineage Cell Proliferation Cell surface Cells Characteristics Clinical Clinical Research Clinical Trials Commit Data Development Disease Disease model Dissection Embryonic Development Employee Strikes Epidermal Growth Factor Receptor Gene Combinations Gene Mutation Generations Genes Genetic Genetic Recombination Genomics Glial Fibrillary Acidic Protein Glioblastoma Glioma Gliosis Goals Grant Growth Headache Human Individual Injection of therapeutic agent Investigation Label Laboratories Lateral MAP Kinase Gene Malignant - descriptor Malignant Glioma Malignant Neoplasms Maps Measures Minor Modeling Molecular Molecular Analysis Molecular Profiling Mus Mutation Neuroglia Neurosciences Oncogenic Outcome PTEN gene Pathway interactions Patients Phenotype Play Population Pre-Clinical Model Pregnancy Primary Brain Neoplasms Property Publishing Radiation Refractory Reporting Resources Risk Role Signal Transduction Signal Transduction Pathway Single Seizures Specificity Staging Stem cells Surveys System Testing The Cancer Genome Atlas Therapeutic Time Tissue Microarray Transgenic Mice Treatment Protocols Tumor Suppressor Genes Uncertainty Undifferentiated Work aldehyde dehydrogenase 1 astrocyte-derived tumor cancer stem cell cell transformation cell type chemotherapy comparative design glioma cell line human disease improved in vivo insight interest mouse model neoplastic cell nerve stem cell nestin protein neuro-oncology neurogenesis novel diagnostics post gamma-globulins progenitor promoter public health relevance relating to nervous system research study response screening stem subventricular zone tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM), the most common type of primary brain tumor, is an aggressive, highly invasive and neurologically destructive tumor considered to be among the deadliest of all human cancers. While it is known that GBM are tumors of glial origin, a continuing and intense debate surrounds whether they arise from differentiated astrocytes, committed astrocyte progenitors or undifferentiated neural stem cells (NSC). The identification of NSC in adult brain has stimulated speculation that poorly differentiated GBM may result from transformation of a NSC or early glial progenitor, rather than progressive dedifferentiation of a mature astrocyte. Distinction among these possibilities may be important in predicting the probable genetic targets involved in malignant transformation and tumor progression. Indeed, the state of glial cell differentiation may be an important factor that governs whether a given genetic mutation exerts its full oncogenic potential. Along these lines, it is possible that there may exist fundamental differences between NSC and astrocytes with regard to the number and types of mutations needed for each cellular compartment to reach a critical cancer threshold of genetic changes for malignant transformation. The major goal of this proposal is to test the hypothesis that both the neural stem cells and terminally differentiated astrocytes are sensitive to malignant transformation by GBM relevant mutations. To test this hypothesis we will use a new generation of transgenic mice which permit temporal control over targeting single or multiple mutations specifically to either NSC or astrocytes and allow the progeny of transformed cells to be traced over time as the tumor progresses. We will perform detailed histological, immunohistochemical and molecular analysis of mouse NSC and astrocyte derived tumors as well as similar analysis of primary human GBM tumors. We anticipate that this information will provide essential insight into GBM tumor cells and their normal cellular counterparts in the brain and that this information will be crucial for generating accurate, faithful mouse models of the disease. PUBLIC HEALTH RELEVANCE: GBM is the deadliest of common human malignancies. The results of these studies could be used to develop new screening tests for GBM cancer, new diagnostic aids, new predictors of outcome and may help identify new targets for chemotherapy and treatment.

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，是一种侵袭性、高度侵袭性和神经破坏性肿瘤，被认为是所有人类癌症中最致命的一种。虽然已知 GBM 是神经胶质来源的肿瘤，但围绕它们是否源自分化的星形胶质细胞、定型星形胶质细胞祖细胞或未分化的神经干细胞 (NSC) 仍存在持续而激烈的争论。成人大脑中 NSC 的鉴定激发了人们的猜测，即低分化的 GBM 可能是由 NSC 或早期神经胶质祖细胞的转化引起的，而不是成熟星形胶质细胞的进行性去分化。区分这些可能性对于预测参与恶性转化和肿瘤进展的可能遗传靶标可能很重要。事实上，神经胶质细胞分化的状态可能是控制给定基因突变是否发挥其全部致癌潜力的重要因素。沿着这些思路，NSC 和星形胶质细胞之间可能存在根本差异，即每个细胞区室达到恶性转化遗传变化的关键癌症阈值所需的突变数量和类型。该提案的主要目标是检验神经干细胞和终末分化星形胶质细胞对 GBM 相关突变导致的恶性转化敏感的假设。为了检验这一假设，我们将使用新一代转基因小鼠，它们允许对特定于 NSC 或星形胶质细胞的单个或多个突变进行时间控制，并允许随着肿瘤进展而随时间追踪转化细胞的后代。我们将对小鼠 NSC 和星形胶质细胞衍生的肿瘤进行详细的组织学、免疫组织化学和分子分析，并对原发性人类 GBM 肿瘤进行类似的分析。我们预计这些信息将为了解 GBM 肿瘤细胞及其在大脑中的正常细胞对应物提供重要的见解，并且这些信息对于生成准确、忠实的疾病小鼠模型至关重要。公共卫生相关性：GBM 是最致命的人类常见恶性肿瘤。这些研究的结果可用于开发 GBM 癌症的新筛查测试、新的诊断辅助工具、新的结果预测因子，并可能有助于确定化疗和治疗的新靶点。