Cellular and molecular basis of malignant astrocytoma

恶性星形细胞瘤的细胞和分子基础

• 批准号: 7432528
• 负责人: YUAN ZHU
• 金额: $ 30.94万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7432528
• 关键词: Accounting; Adult; Anaplastic astrocytoma; Apoptosis; Astrocytes; Astrocytoma; Brain; Brain Neoplasms; Cell Proliferation; Cells; Central Nervous System Neoplasms; Characteristics; Development; Disease; Gene Mutation; Gene Silencing; Genetic; Genetically Engineered Mouse; Glioblastoma; Goals; Growth; Human; Image Analysis; Invaded; Invasive; Lesion; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mediating; Modality; Modeling; Molecular; Molecular Genetics; Mutant Strains Mice; Mutation; NF1 gene; Nature; Neoplasms; Neuraxis; Neurofibromatosis 1; Neurons; Oligodendroglia; Operative Surgical Procedures; Physiological; Play; Predisposition; Protein p53; Radiation; Regulation; Research Personnel; Resistance; Role; Solid Neoplasm; Staging; System; TP53 gene; Testing; Tetracycline; Tetracyclines; Therapeutic; Tumor Suppressor Genes; Work; base; brain cell; brain tissue; cell type; chemotherapy; insight; mouse model; nerve stem cell; nestin protein; neurosurgery; outcome forecast; prevent; programs; relating to nervous system; residence; response; trait; tumor; tumorigenic

DESCRIPTION (provided by applicant): Astrocytomas are the most common primary brain tumors and account for more than 60% of all primary central nervous system (CMS) neoplasms. The most malignant form of astrocytoma (grade IV astrocytoma), also known as glioblastoma multiforme (GBM), is 1 of the most aggressive human cancers with a median survival of less than 1 year. Unfortunately, this prognosis has not changed significantly over the past 2 decades, despite advances in neurosurgery, radiation and chemotherapy. 2 characteristic features of malignant astrocytomas play a major role in defining the deadly nature of the disease. First, unlike most human solid tumors, astrocytoma cells extensively invade normal brain tissue even at the low-grade stage, which essentially prevents surgical cure. Second, low-grade astrocytomas have a high propensity to transform into GBMs, which are resistant to all of the current therapeutic modalities. Thus, 1 of the major challenges for treating malignant astrocytomas is to understand the cellular and molecular basis that underlies the highly invasive nature of astrocytoma cells. Particularly, (1) it remains elusive what cell type(s) in the brain gives rise to malignant astrocytoma, (2) insights have been slower to emerge regarding how the specific genetic defects contribute to the abnormal phenotypic traits of astrocytoma cells, despite recent advances in the identification of genetic lesions associated with the development of malignant astrocytomas. Thus, the goals of the specific aims described in this proposal is to use genetic, molecular and cellular approaches to determine whether neural stem cells (NSCs) in the adult brain are the cell-of-origin for malignant astrocytoma. Specifically, we will determine (1) whether tumor suppressors p53 and Neurofibromatosis type 1 (NF1) play physiological roles in regulating NSC proliferation, apoptosis and differentiation in the adult brain and (2) whether malignant astrocytoma can be induced when p53 and NF1 mutations are specifically targeted into NSCs in the adult brain.

描述（由申请人提供）：星形细胞瘤是最常见的原发性脑肿瘤，占所有原发性中枢神经系统（CMS）肿瘤的 60% 以上。最恶性的星形细胞瘤（IV 级星形细胞瘤），也称为多形性胶质母细胞瘤 (GBM)，是最具侵袭性的人类癌症之一，中位生存期不到 1 年。不幸的是，尽管神经外科、放疗和化疗取得了进展，但这种预后在过去 20 年来并未发生显着改变。恶性星形细胞瘤的 2 个特征在确定该疾病的致命性方面发挥着重要作用。首先，与大多数人类实体瘤不同，星形细胞瘤细胞即使在低级别阶段也会广泛侵入正常脑组织，这基本上阻碍了手术治愈。其次，低级别星形细胞瘤极有可能转化为 GBM，而 GBM 对当前的所有治疗方式均具有耐药性。因此，治疗恶性星形细胞瘤的主要挑战之一是了解星形细胞瘤细胞高度侵袭性的细胞和分子基础。特别是，（1）大脑中哪些细胞类型导致恶性星形细胞瘤仍然难以捉摸，（2）尽管最近在识别与恶性星形细胞瘤发展相关的遗传病变方面取得了进展，但关于特定遗传缺陷如何导致星形细胞瘤细胞异常表型特征的见解却较慢地出现。因此，本提案中描述的具体目标的目标是利用遗传、分子和细胞方法来确定成人大脑中的神经干细胞（NSC）是否是恶性星形细胞瘤的起源细胞。具体来说，我们将确定（1）肿瘤抑制因子p53和1型神经纤维瘤病（NF1）是否在调节成人大脑中NSC增殖、凋亡和分化中发挥生理作用；（2）当p53和NF1突变特异性靶向成人大脑中的NSC时是否可以诱导恶性星形细胞瘤。