Role of Olig Genes in Human Gliomagenesis

Olig 基因在人类胶质瘤发生中的作用

• 批准号: 7320230
• 负责人: Santosh Kesari
• 金额: $ 14.05万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320230
• 关键词: Address; Affect; Binding; Biological; Biological Models; Biology; Brain Neoplasms; CDKN1A gene; Cancer Center; Cell Cycle; Cells; Chromatin; Clinical; Clinical Protocols; Collection; Complement; Confounding Factors (Epidemiology); Development; Diffuse; Epidermal Growth Factor Receptor; Family; Genes; Genetic; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; Human; In Situ Hybridization; In Vitro; Laboratories; Lead; Learning; Lentivirus Vector; Lesion; Life; Link; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Methodology; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Neurobiology; Neuroglia; Neurons; Operative Surgical Procedures; PTEN gene; Patients; Phenotype; Population; Postdoctoral Fellow; RNA Interference; RNAi vector; Range; Reagent; Research; Research Personnel; Role; Sampling; Series; Services; Specific qualifier value; Stem cells; Techniques; Testing; Tumor Stem Cells; Woman; Work; cancer stem cell; chromatin immunoprecipitation; human disease; improved; in vivo Model; inhibitor/antagonist; insight; loss of function; malignant phenotype; mortality; mouse model; mutant; nerve stem cell; nervous system disorder; neuro-oncology; neuropathology; novel; oncoprotein p21; progenitor; promoter; research study; social; transcription factor; tumor; tumorigenic; young adult

DESCRIPTION (provided by applicant): A small population of CD133 (a stem cell marker) positive "tumor stem cells" has been recently shown to embody the tumorigenic phenotype of human glioblastomas. In preliminary studies, we have shown 1) that 100% of CD133-positive stem cells in fresh surgical isolates of human glioma express the gliogenic transcription factor OLIG2, 2) that OLIG2 is essential for tumor formation in a mouse model of glioma that emulates human gliomas at a genetic level, 3) that the cell cycle inhibitor P21 is derepressed in OLIG2 deficient mouse neural stem cells by expression analysis, and 4) that OLIG2 binds to P21 promoter in human glioblastoma by chromatin immunoprecipitation thus linking OLIG2 to the cell cycle regulatory apparatus. My objectives are to test the hypothesis that OLIG2 is essential for the malignant growth of human CD133-positive human glioma stem cells in in vitro and in vivo model systems and to elucidate the mechanism by which OLIG2 affects tumor stem cells. The Specific Aims are as follows: Aim 1 is to test the prediction that P21 expression segregates from OLIG2 in diffuse human gliomas by in situ hybridization and immunofluorescent methods on surgical isolates. Aim 2 is to test the prediction that suppression of OLIG2 will stimulate the expression of P21 in human glioma stem cells and suppress their malignant phenotype using RNAi lentiviral vectors against OLIG2. Aim 3 is to test the prediction that P21 is epistatic to OLIG2 for maintenance of the malignant phenotype by determining whether ectopic P21 can suppress the transformed phenotype of CD133-positive human glioma stem cells as per Aim 2. Aim 4 is to expand our repertoire of direct genetic targets of OLIG2 through chromatin immunoprecipitation-tiled array ("ChlP-on-chip") analysis of OLIG2 interactions in human CD133-positive stem cells. Over the term of this K08 I will learn and develop new techniques, approaches, and methodologies that will allow me to develop into an independent investigator. My long-range goals are to study how normal neuro-developmental mechanisms can be subverted to form brain cancer and to develop rational approaches to target these mechanisms to improve survival of our brain tumor patients. These studies may additionally provide insights into other aspects of clinical neurobiology given the broad involvement of glia in many neurological disorders. Relevance: Glioblastoma is the most common type of brain tumor affecting young adults in the prime of their social and family life causing tremendous morbidity and mortality for which there is no cure. The goal of this application is to elucidate the role of OLIG2 in human glioma stem cells with the aim of discovering a new target(s) for the treatment of this devastating cancer.

描述（由申请人提供）：最近已证明少数CD133（干细胞标记）阳性“肿瘤干细胞”体现了人胶质母细胞瘤的肿瘤表型。 In preliminary studies, we have shown 1) that 100% of CD133-positive stem cells in fresh surgical isolates of human glioma express the gliogenic transcription factor OLIG2, 2) that OLIG2 is essential for tumor formation in a mouse model of glioma that emulates human gliomas at a genetic level, 3) that the cell cycle inhibitor P21 is derepressed in OLIG2 deficient mouse neural stem cells by expression analysis, 4）OLIG2通过染色质免疫沉淀与人胶质母细胞瘤中的P21启动子结合，从而将Olig2与细胞周期调节仪联系起来。我的目标是检验以下假设：Olig2对于在体外和体内模型系统中人类CD133阳性人神经胶质瘤干细胞的恶性生长至关重要，并阐明了寡糖影响肿瘤干细胞的机制。具体目的如下：目标1是测试以下预测，即通过原位杂交和外科分离株上的原位杂交和免疫荧光方法，p21表达从弥漫性人神经胶质瘤中分离出来。目的2是测试抑制Olig2将刺激P21在人神经胶质瘤干细胞中的表达的预测，并使用RNAi慢病毒载体针对Olig2抑制其恶性表型。 Aim 3 is to test the prediction that P21 is epistatic to OLIG2 for maintenance of the malignant phenotype by determining whether ectopic P21 can suppress the transformed phenotype of CD133-positive human glioma stem cells as per Aim 2. Aim 4 is to expand our repertoire of direct genetic targets of OLIG2 through chromatin immunoprecipitation-tiled array ("ChlP-on-chip") analysis of人CD133阳性干细胞中的Olig2相互作用。在这个K08的任期内，我将学习和开发新技术，方法和方法，使我能够发展成为独立的研究者。我的远程目标是研究如何颠覆正常的神经发育机制以形成脑癌，并开发出靶向这些机制以提高脑肿瘤患者生存的合理方法。鉴于神经胶质在许多神经系统疾病中的广泛参与，这些研究可能还可以提供对临床神经生物学其他方面的见解。 相关性：胶质母细胞瘤是影响年轻人的社会和家庭生活的最常见类型的脑肿瘤类型，导致无法治愈的巨大发病率和死亡率。该应用的目的是阐明寡聚2在人神经胶质瘤干细胞中的作用，目的是发现一种新靶标，以治疗这种毁灭性的癌症。