An investigation of Radial Glia as the source of Ependymoma Stem Cells

放射状胶质细胞作为室管膜瘤干细胞来源的研究

• 批准号: 9069142
• 负责人: Richard Gilbertson
• 金额: $ 15.96万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069142
• 关键词: Accounting; Binding; Biological; Biological Assay; Biological Markers; Biology; Brain; Brain Neoplasms; Cataloging; Catalogs; Cells; Cellular biology; Clinic; Clinical; Clinical Trials; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease model; Drug Targeting; Ependymoma; Face; Failure; Formalin; Funding; Future; Gene Expression; Genes; Genome; Genomic approach; Genomics; Histologic; Human; Investigation; Knowledge; Malignant Neoplasms; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Neuraxis; Neuroglia; Oncogenes; Oncogenic; Operative Surgical Procedures; Paraffin Embedding; Patient Selection; Patients; Phase; Population; Pre-Clinical Model; Preclinical Drug Evaluation; Predisposition; Process; Radial; Research; Research Personnel; Resources; Role; Series; Signal Transduction; Source; Spinal; Spinal Cord; Stem cells; Technology; Testing; Therapeutic; Therapy Clinical Trials; Tissues; Tumor Suppressor Genes; Virus; Work; base; chemotherapy; data integration; design; disorder subtype; drug development; genetic analysis; in vivo; innovation; irradiation; mortality; mouse model; nerve stem cell; novel; outcome forecast; screening; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Ependymomas are tumors of the brain and spinal cord. Treatment approaches and mortality rates for this disease have changed little over the last twenty years, highlighting the great need for new therapies. Histologic similarities among ependymomas have led investigators to treat these tumors as a single entity; but we have shown that ependymomas from different regions of the central nervous system include discrete clinical and molecular subtypes, suggesting they are different diseases. Thus, contemporary efforts to cure all patients with ependymoma must be concerned with understanding the biological basis of these disease subtypes, and where necessary, developing subtype-specific therapies. During the last funding cycle we developed a cross- species genomics approach that characterized genomic subtypes of human ependymoma and matched these with neural stem cells in the mouse to generate accurate models of the disease. We will build on this work to complete three Specific Aims designed to test the central hypothesis that 'Ependymoma subtypes are driven by distinct cell signals that can be targeted for therapeutic gain.' Aim 1 will employ new 'virus-pool' screens to test the in vivo oncogenic role of the top 90 candidate oncogenes and 40 tumor suppressor genes that we previously identified in ependymoma. We will thereby generate a 'clinic' of mice that recapitulate the full spectrum on human ependymoma subtypes. Aim 2 will interrogate the models developed in Aim 1 using high- throughput drug screens, kinome-wide binding and cell biology assays to pinpoint the key cell signals that maintain each ependymoma subtype that might therefore serve as therapeutic targets. Integration of these data with genetic analyses of human and mouse tumors will further validate candidate drug targets. Future clinical trials of therapies that target signals identified in Aim 2 will demand the selection of patients with the appropriate disease subtype. Therefore, Aim 3 will develop a robust Affymetrix Quantigene assay to reliably and rapidly diagnose ependymoma subtypes using formalin fixed paraffin embedded tissue.

描述（由申请人提供）：室管膜瘤是脑和脊髓的肿瘤。在过去二十年里，这种疾病的治疗方法和死亡率几乎没有变化，这凸显了对新疗法的巨大需求。室管膜瘤之间的组织学相似性使得研究人员将这些肿瘤视为一个单一的实体。但我们已经证明，来自中枢神经系统不同区域的室管膜瘤包括不同的临床和分子亚型，表明它们是不同的疾病。因此，当代治愈所有室管膜瘤患者的努力必须关注了解这些疾病亚型的生物学基础，并在必要时开发亚型特异性疗法。在上一个资助周期中，我们开发了一种跨物种基因组学方法，该方法描述了人类室管膜瘤的基因组亚型，并将其与小鼠的神经干细胞相匹配，以生成该疾病的准确模型。我们将在这项工作的基础上完成三个具体目标，旨在测试“室管膜瘤亚型是由不同的细胞信号驱动的，这些信号可以针对治疗效果”这一中心假设。目标1将 采用新的“病毒库”筛选来测试我们之前在室管膜瘤中鉴定的前 90 种候选癌基因和 40 种肿瘤抑制基因的体内致癌作用。因此，我们将建立一个小鼠“诊所”，概括人类室管膜瘤亚型的全谱。目标 2 将使用高通量药物筛选、全激酶组结合和细胞生物学测定来询问目标 1 中开发的模型，以查明维持每种室管膜瘤亚型的关键细胞信号，从而可以作为治疗靶点。将这些数据与人类和小鼠肿瘤的遗传分析相结合将进一步验证候选药物靶点。针对目标 2 中确定的信号的疗法的未来临床试验 将需要选择具有适当疾病亚型的患者。因此，Aim 3 将开发一种强大的 Affymetrix Quantigene 检测方法，使用福尔马林固定石蜡包埋的组织可靠、快速地诊断室管膜瘤亚型。