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The DNA Damage Response and Tumorigenesis in the Brain

大脑中的 DNA 损伤反应和肿瘤发生

基本信息

批准号：
8854876
负责人：
PETER J MCKINNON
金额：
$ 45.28万
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 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8854876
关键词：
Accounting Address B-Cell Lymphomas Base Excision Repairs Bioinformatics Biology Brain Brain Neoplasms Cancer Etiology Cell Proliferation Cessation of life Child Childhood Childhood Brain Neoplasm Childhood Central Nervous System Neoplasm Chromatin Chromatin Structure Chromosome Fragile Sites DNA DNA Damage DNA Repair DNA Repair Pathway DNA Sequence Alteration DNA strand break Defect Development Disease Epigenetic Process Event Gene Cluster Gene Expression Genetic Genome Genome Stability Genomic Instability Glioblastoma Glioma Gliomagenesis Heterogeneity Histology Histone H3 Histones Histopathology Human Hypersensitivity Individual Laboratories Lesion Link Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Modeling Molecular Molecular Biology Molecular Profiling Mus Mutation Neoplasms Nervous system structure Nonhomologous DNA End Joining PDGFRA gene Pathogenesis Pathway interactions Patients Population Predisposition Proteins Proto-Oncogenes Relative (related person)Research Series Signal Transduction Solid Staging Stress Survival Rate Therapeutic Topoisomerase Tumor Biology Tumor Suppression base cell type genome integrity homologous recombination human disease improved in vivo member mouse model mutant nerve stem cell neurodevelopment neurogenesis new therapeutic target novel outcome forecast prevent progenitor programs relating to nervous system repaired research study response spatiotemporal stem targeted treatment telomere therapeutic target tumor tumorigenesis

项目摘要

Summary - Project 2 Brain tumors are the most common solid malignancies of childhood and are a leading cause of cancer-related death in children. 15-20% of pediatric CNS tumors are high-grade gliomas (HGG), and individuals with these tumors have a 2-year survival rate of 10-30%. Despite extensive research into the molecular basis of gliomagenesis, current therapies remain ineffective, and the majority of patients die from their disease. More effective therapeutic strategies are likely to come from a detailed understanding of glioma pathogenesis. We have developed a unique series of new HGG mouse models, relevant to the human disease, which are characterized by a range of histopathology reflective of the specific defect in the DNA damage response. In Aim 1 of this proposal we will determine the genomic alterations and gene expression profiles that underpin these gliomas, particularly in the context of human disease and other mouse glioma models, either established or under development in other projects in this program. We will also determine the basis for tumor heterogeneity in these models by ascertaining the detailed developmental origins of these gliomas and the relative susceptibility of different neural progenitors to transformation. These analyses will illuminate critical aspects of the pathogenesis of gliomas for which there is a paucity of definitive information. Finally, we will also determine cooperativity in these models with other mutations found in human pediatric HGG, including histone H3 mutations, taking advantage of novel models generated by other projects within the program. In Aim 2 we propose experiments to establish which DNA repair pathways are critical for genome stability at different cortical progenitor stages and how this is linked to chromatin. Because histone mutations and other epigenetic alterations have recently been identified as causative molecular changes in pediatric HGG, our study will be of central importance for understanding connections between DNA damage signaling, epigenetics and tumorigenesis. In Aim 3 we will determine if DNA breaks associated with early replicating fragile sites account for DNA structural alterations central to gliomagenesis. Collectively, findings from this study will provide fundamental new information to delineate glioma biology that will be important for developing targeted therapy for these diseases.

摘要-项目二