Molecular Pathogenesis of Pediatric High Grade Glioma

儿童高级别胶质瘤的分子发病机制

基本信息

批准号：
9277197
负责人：
SUZANNE J BAKER
金额：
$ 47.24万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9277197
关键词：
Adult Adult Glioblastoma Age Automobile Driving Bioinformatics Biological Biological Models Brain Brain Stem CRISPR/Cas technology ChIP-seq Child Childhood Childhood Brain Neoplasm Childhood Central Nervous System Neoplasm Childhood Glioblastoma Childhood Glioma Chromatin Complex DNA Methylation Data Development Diagnosis Diffuse Diffuse intrinsic pontine glioma Disease Elderly Epidermal Growth Factor Receptor Epigenetic Process Frequencies Funding Gene Expression Gene Expression Profile Gene Expression Profiling Genetic Genomic Segment Glioblastoma Glioma Gliomagenesis Goals Histone H3 Histones Human In Vitro Induced Mutation Knock-in Mouse Knock-out Lateral Libraries Location LoxP-flanked allele Maintenance Malignant Neoplasms Missense Mutation Modeling Molecular Molecular Analysis Molecular Profiling Monitor Mus Mutation Neoplasms PDGFRA gene Pathogenesis Patients Pattern Post-Translational Protein Processing Preclinical Testing Predisposition Receptor Protein-Tyrosine Kinases Recurrence Role Somatic Mutation Subgroup Survival Rate Therapeutic Therapeutic Intervention Transgenic Mice Xenograft procedure cell type epigenetic regulation epigenomics genome editing genome-wide genome-wide analysis improved in vivo inhibitor/antagonist insight knock-down medulloblastoma mouse model mutant neurodevelopment neuropathology outcome forecast pre-clinical regional difference research clinical testing small hairpin RNA therapeutic target transcription factor tumor tumorigenesis young adult

项目摘要

Summary – Project 1 The goals of this project are to advance understanding of the pathogenesis of pediatric high-grade glioma (HGG), define connections between neural development and gliomagenesis, and generate improved model systems with specific relevance to pediatric HGG. Pediatric HGGs comprise 15-20% of all pediatric CNS tumors, and remain largely incurable, with a two year survival rate of less than 30%. A subset of pediatric HGGs arise within the brainstem as diffuse intrinsic pontine glioma (DIPG), a tumor that arises almost exclusively in children with a two year survival of less than 10%. During the last funding period, we developed improved mouse models of HGG, and conducted in-depth genome-wide studies of pediatric HGG including DIPG. Results from our group and others showed distinct differences in the genetic alterations driving childhood and adult HGG. Most strikingly, recurrent somatic mutations in histone H3 are found in 78% of DIPGs and 36% of HGGs, but only rarely in young adults with glioblastoma, and not in older adult glioblastoma patients. Building on this progress, we propose to determine why histone H3 mutations have a unique selective advantage in the context of developing brain, to determine their contribution to tumorigenesis and the epigenomic landscape of pediatric HGG, and to develop improved model systems of pediatric HGG for biological studies and preclinical testing. Our studies are integrated with those in the other projects that explore mechanisms and genetic and epigenetic signatures driving glioma and medulloblastoma formation, and the identification of therapeutic targets for these devastating diseases. The project receives essential support from the Bioinformatics and Neuropathology Cores for the complex integrated analysis of molecular and histopathological features of tumors generated in model systems and comparisons with primary human tumors.

摘要 - 项目1 该项目的目标是提高对小儿高度神经胶质瘤的发病机理的了解（HGG），定义神经元发育与神经胶质作用之间的联系，并产生改进的模型与儿科HGG具有特定相关性的系统。小儿HGGS占所有小儿中枢神经系统的15-20％肿瘤，并且在很大程度上无法治愈，两年的存活率小于30％。小儿的子集 HGGS在脑干内出现，弥漫仅在两年生存率的儿童中，不到10％。在最后的资金期间，我们开发了改善了HGG的小鼠模型，并对小儿HGG进行了深入的全基因组研究 dipg。我们小组和其他人的结果在驱动遗传改变方面存在明显差异童年和成人HGG。最引人注目的是，在78％ DIPGS和36％的HGG，但很少有胶质母细胞瘤的年轻人，而不是老年人胶质母细胞瘤患者。在这一进展的基础上，我们建议确定为什么组蛋白H3突变具有独特在发展大脑的背景下，选择性优势，以确定它们对肿瘤发生的贡献和小儿HGG的表观基因组景观，并开发改进的小儿HGG模型系统生物学研究和临床前测试。我们的研究与其他项目中的研究集成在一起探索机制，遗传和表观遗传特征，促进胶质瘤和髓母细胞瘤形成，以及确定这些毁灭性疾病的治疗靶标。该项目收到必不可少的生物信息学和神经病理学核心的支持，用于分子的复杂综合分析模型系统中产生的肿瘤的组织病理学特征以及与原代人的比较肿瘤。