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：
8375486
负责人：
SUZANNE J BAKER
金额：
$ 30.75万
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/8375486
关键词：
Adult Astrocytes Biological Biological Assay Biological Models Brain Brain Neoplasms Brain Stem Glioma Cell Culture Techniques Characteristics Child Childhood Childhood Brain Neoplasm Classification Clinical Collection Data Diagnosis Diffuse Disease Foundations Freezing Frequencies Funding Gene Deletion Gene Expression Profile Gene Mutation Genes Genetic Genomics Genotoxic Stress Glioma Gliomagenesis Goals Growth In Vitro Knockout Mice Location Malignant Neoplasms MicroRNAs Microarray Analysis Modeling Molecular Molecular Abnormality Molecular Analysis Molecular Genetics Mus Mutation Neoplasms Neurons Oncogenes Pathogenesis Pathway interactions Patients Pattern Penetrance Pontine structure Progress Review Group Recurrence Regulation Reporting Research Resistance Resolution Sampling Signal Pathway Signal Transduction Pathway Subgroup Suppressor Genes System Testing Therapeutic Agents Therapeutic Intervention Tissue Model Tumor Suppressor Genes Tumor Suppressor Proteins base density gene function genome-wide analysis human tissue improved in vitro Model in vivo in vivo Model inhibitor/antagonist knock-down mouse model novel novel therapeutics outcome forecast overexpression programs research clinical testing small molecule therapeutic target tumor tumorigenesis

项目摘要

The goals of this project are to advance understanding of the molecular pathogenesis of pediatric high grad glioma (HGG), identify targets for therapeutic intervention and generate improved model systems for biological study and pre-clinical testing. Pediatric HGGs comprise 15-20% of all pediatric CMS tumors, and carry an abysmal prognosis, with 70-90% of patients dying within 2 years of diagnosis. While the molecular genetics of adult HGG has been investigated extensively, much less is known about the pediatric disease, in large part due to limiting patient samples. The lack of tumor material for research is especially challenging for HGG arising in the pons, termed diffuse brainstem gliomas (BSG), because they are not treated surgically. A comprehensive high-resolution molecular analysis of a large collection of pediatric HGG has never been reported. Importantly, there are distinct differences in the frequency of specific gene mutations between pediatric and adult HGG, indicating that targeted therapeutic strategies developed for adults may not be optimal approaches for children. The foundation for our proposal includes novel in vitro and in vivo models for HGG developed during the first funding period, and a unique large collection of rare pediatric HGG samples for biological studies. We will complete a comprehensive high resolution analysis of pediatric HGG, identify candidate oncogenes and tumor suppressor genes for HGG and test their contribution to astrocytic tumorigenesis, and use novel mouse models to dissect tumor suppressor function in gliomagenesis in vivo. Our studies will be integrated with others in this program project to identify unique cancer pathways underlying pediatric HGG and common pathways leading to pediatric brain tumors.

该项目的目标是提高对小儿高生神经胶质瘤（HGG）分子发病机制的了解，确定治疗干预的靶标，并为生物学研究和临床前测试产生改进的模型系统。小儿HGGS占所有小儿CMS肿瘤的15-20％，并具有糟糕的预后，其中70-90％的患者在诊断后的2年内死亡。尽管已经对成年HGG的分子遗传学进行了广泛的研究，但对小儿疾病的了解少得多，这在很大程度上是由于限制了患者样本。缺乏研究肿瘤材料尤其具有挑战性，对于PON中引起的HGG，称为弥漫性脑干神经胶质瘤（BSG），因为它们没有通过外科手术进行治疗。从未报道过大量小儿HGG的全面高分辨率分子分析。重要的是，小儿和成人HGG之间特定基因突变的频率存在明显差异，这表明针对成年人开发的有针对性的治疗策略可能不是儿童的最佳方法。我们建议的基础包括在第一个资金期间开发的HGG的新型体外和体内模型，以及独特的稀有儿科HGG样品，用于生物学研究。我们将完成对小儿HGG的全面高分辨率分析，鉴定候选肿瘤基因和肿瘤抑制基因，以进行HGG并测试其对星形胶质细胞肿瘤发生的贡献，并使用新颖的小鼠模型在体内胶质摄起症中剖析肿瘤抑制器功能。我们的研究将与该计划项目中的其他人集成，以鉴定小儿HGG的基本癌症途径和导致小儿脑肿瘤的常见途径。