Molecular Pathogenesis of Pediatric High-grade Glioma

儿童高级别胶质瘤的分子发病机制

• 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
• 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

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.

该项目的目标是增进对儿科高级别胶质瘤 (HGG) 分子发病机制的了解，确定治疗干预的目标，并为生物学研究和临床前测试生成改进的模型系统。儿童 HGG 占所有儿童 CMS 肿瘤的 15-20%，预后极差，70-90% 的患者在诊断后 2 年内死亡。虽然成人 HGG 的分子遗传学已得到广泛研究，但对儿科疾病的了解却少之又少，这在很大程度上是由于患者样本有限。对于脑桥中出现的 HGG（称为弥漫性脑干胶质瘤 (BSG)）来说，缺乏用于研究的肿瘤材料尤其具有挑战性，因为它们无法通过手术治疗。对大量儿科 HGG 进行全面的高分辨率分子分析从未有过报道。重要的是，儿童和成人 HGG 之间的特定基因突变频率存在明显差异，这表明为成人开发的靶向治疗策略可能不是儿童的最佳方法。我们提案的基础包括在第一个资助期间开发的新型 HGG 体外和体内模型，以及用于生物学研究的独特的大量罕见儿科 HGG 样本。我们将完成对儿科 HGG 的全面高分辨率分析，确定 HGG 的候选癌基因和抑癌基因，并测试它们对星形细胞肿瘤发生的贡献，并使用新型小鼠模型来剖析体内胶质瘤发生中的抑癌功能。我们的研究将与该项目中的其他研究相结合，以确定儿科 HGG 背后的独特癌症途径和导致儿科脑肿瘤的常见途径。