Cellular and Genetic Basis of Anaplastic Medulloblastoma

间变性髓母细胞瘤的细胞和遗传基础

• 批准号: 8251118
• 负责人: Michael D. Taylor
• 金额: $ 61.87万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-04 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251118
• 关键词: Address; Age; Aggressive behavior; Anaplasia; Anaplastic Cell; Animal Model; Behavior; Candidate Disease Gene; Cells; Cerebellum; Cerebrospinal Fluid; Child; Childhood Brain Neoplasm; Complementary DNA; DNA Transposable Elements; Data; Data Set; Disease; Epigenetic Process; Exhibits; Freezing; Gender; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Genomics; Growth; Histology; Human; Institution; Malignant - descriptor; Malignant neoplasm of brain; Mediating; Metastatic Neoplasm to the Leptomeninges; Methylation; Modeling; Molecular; Monitor; Mus; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phenotype; Positioning Attribute; Prevention; Primary Neoplasm; Property; Research Personnel; Retroviridae; Sampling; Signaling Pathway Gene; Site; Sleeping Beauty; Subgroup; Tissues; Transplantation; base; experience; genome-wide; improved; in vivo; mRNA Expression; medulloblastoma; mouse model; neoplastic cell; neurodevelopment; outcome forecast; prevent; public health relevance; small hairpin RNA; stem cell biology; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit large cell/anaplastic (LCA) histology usually fail therapy and die from their disease. Improved approaches to treating these patients are likely to come from a deeper understanding of LCA tumors, including their aggressive growth properties and their invasive and metastatic behavior. Unfortunately, human LCA MB tissue is difficult to obtain, and existing genetically engineered mouse (GEM) models of MB rarely display anaplasia or metastasis. To address this problem, we have collected >100 human LCA MBs, including paired samples of primary/metastatic tumors. In addition, we have generated GEM and transplant-based models of LCA MB, and mobilized the transposable element Sleeping Beauty (SB) to promote anaplasia and metastasis in these models. Through analysis of our human and murine datasets, we propose to identify the cells and genes that drive progression in LCA medulloblastoma. This application brings together investigators from three institutions, with collective experience in neural development, stem cell biology and genomics of both human and murine MB. Our complementary backgrounds and expertise uniquely position us to investigate the cellular and molecular basis of LCA MB, and will ultimately allow us to develop more effective approaches to targeting these aggressive tumors. PUBLIC HEALTH RELEVANCE: The proposed studies focus on large cell/anaplastic medulloblastoma, a highly malignant pediatric brain tumor with an extremely poor prognosis. By identifying the cells and genes responsible for the aggressive behavior of this tumor, we hope to develop more effective approaches to therapy.

描述（由申请人提供）：髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤。肿瘤表现出较大的细胞/变性（LCA）组织学的患者通常会失败治疗并死于疾病。改进的治疗这些患者的方法可能来自对LCA肿瘤的更深入的了解，包括其侵略性生长特性及其侵入性和转移行为。不幸的是，人体LCA MB组织难以获得，现有的MB的遗传工程小鼠模型很少表现出阿拉帕斯氏症或转移。为了解决这个问题，我们收集了> 100个人类LCA MB，包括原发性/转移性肿瘤的配对样品。此外，我们已经生成了LCA MB的GEM和基于移植的模型，并动员了可转移元素睡美（SB），以在这些模型中促进异常和转移。通过对人类和鼠数据集的分析，我们建议鉴定驱动LCA髓母细胞瘤进展的细胞和基因。该应用程序汇集了来自三个机构的研究人员，在人类和鼠MB的神经发育，干细胞生物学和基因组学方面具有集体经验。我们的互补背景和专业知识独特地定位了我们研究LCA MB的细胞和分子基础，并最终将使我们能够开发出更有效的方法来靶向这些侵略性肿瘤。 公共卫生相关性：拟议的研究集中于大细胞/肿瘤髓母细胞瘤，这是一种高度恶性的小儿脑肿瘤，预后极不良。通过确定负责该肿瘤侵略行为的细胞和基因，我们希望开发更有效的治疗方法。