Embryonal Brain Tumor Networks

胚胎脑肿瘤网络

基本信息

批准号：
9280874
负责人：
Ernest Fraenkel
金额：
$ 32.49万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9280874
关键词：
Affect Algorithms Behavior Biological Brain Neoplasms Cancer Biology Cancer Etiology Cell Culture Techniques ChIP-seq Childhood Childhood Brain Neoplasm Clinical Collaborations Computational Technique Computing Methodologies Copy Number Polymorphism DNA Sequence Alteration Data Data Set Environment Epigenetic Process Formalin Gene Expression Genes Genetic Genetic Transcription Genome Genomics Histologic Hospitals Human Immunohistochemistry Impairment Link Malignant Neoplasms Massive Parallel Sequencing Measures Methods MicroRNAs Modeling Molecular Molecular Profiling Mutation Nervous System Physiology Neuraxis Neurocognitive Neurologic Oncogenic Outcome Paraffin Embedding Pathway interactions Patients Pattern Pediatric Neoplasm Phenotype Plant Roots Prize Protein Analysis Proteins Reverse Transcriptase Polymerase Chain Reaction Sampling Set protein Signal Pathway Slide Somatic Mutation Survival Rate Survivors System Systems Biology Testing Time Training Translational Research Tumor Cell Line Work base bisulfite sequencing chromatin immunoprecipitation data modeling drug development epigenome epigenomics exome sequencing forest genomic data individual patient innovation knock-down mRNA Expression medulloblastoma mutant network models new therapeutic target novel novel strategies novel therapeutic intervention overexpression programs protein expression protein function public health relevance response small hairpin RNA small molecule software development therapeutic candidate therapeutic target tool transcriptome transcriptome sequencing treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): We propose an innovative, systems biology approach to uncover new therapeutic strategies for childhood embryonal tumors. Our project is a collaboration between labs in two separate Integrative Cancer Biology Program (ICBP) centers and a leading hospital-based translational research lab that is not within the ICBP network. Embryonal tumors are the most common central nervous system malignancies in childhood, and there is a pressing need for better therapies. Current survival rates range from 30 - 80%, and nearly all survivors have impaired neurological and neurocognitive function. Extensive genomic analysis of medulloblastomas, the most common embryonal tumors, failed to identify "driver genes" that could explain the origin of most tumors or suggest new strategies. Nevertheless, these tumors can be grouped into a small number of subtypes that share transcriptional patterns and clinical outcomes. We believe that it is time for a fundamentally new approach that seeks oncogenic "driver pathways" rather than "driver genes." As many different genomic changes can all affect the same driver pathway, such pathways cannot be uncovered by looking for recurring genomic changes. Rather, we will use a systems biology approach to identify these oncogenic driver pathways. We will collect comprehensive datasets in human medulloblastoma tumors and cell lines by measuring mutations, copy number variations, mRNA expression, miRNA expression and epigenomic data. We will then construct network models identifying shared pathways altered across many patients within a subtype. Finally, we will functionally test driver pathways nominated from the network modeling. By merging these diverse genomic and transcriptional data collected from tumors of individual patients, we will have an unprecedented ability to uncover the root causes of cancer, providing new therapeutic strategies. The collective expertise of our collaboration provides a unique environment for solving this critical barrier in cancer, by combining strengths in analyzing genomic data, modeling signaling pathways and transcriptional regulatory networks and clinical expertise in embryonal brain tumors. Together, we will generate and merge all types of transcriptional, genomic and epigenomic data, extract biologically-relevant network models and experimentally validate novel drug targets.

描述（由申请人提供）：我们提出了一种创新的系统生物学方法，以发现儿童胚胎肿瘤的新治疗策略。我们的项目是两个独立的综合癌症生物学计划（ICBP）中心的实验室与不在ICBP网络中的领先的基于医院的转化研究实验室之间的合作。胚胎肿瘤是童年中最常见的中枢神经系统恶性肿瘤，并且迫切需要更好的疗法。当前的存活率范围为30-80％，几乎所有幸存者都损害了神经学和神经认知功能。对髓母细胞瘤（最常见的胚胎肿瘤）的广泛基因组分析未能鉴定出可以解释大多数肿瘤起源或提出新策略的“驱动基因”。然而，这些肿瘤可以分为少数共享转录模式和临床结果的亚型。我们认为，现在是时候采用一种新的新方法，寻求致癌的“驱动器途径”而不是“驱动基因”。由于许多不同的基因组变化都会影响相同的驱动程序途径，因此无法通过寻找反复出现的基因组变化来发现这种途径。相反，我们将使用系统生物学方法来识别这些致癌驱动器途径。我们将通过测量突变，拷贝数变化，mRNA表达，miRNA表达和表观基因组数据来收集人类髓母细胞瘤肿瘤和细胞系中的全面数据集。然后，我们将构建网络模型，以识别亚型中许多患者的共享途径发生了变化。最后，我们将在功能上测试从网络建模提名的驱动程序路径。通过合并从个别患者肿瘤收集的这些多样化的基因组和转录数据，我们将具有空前的癌症根本原因，提供新的治疗策略。我们合作的集体专业知识为解决癌症的关键障碍提供了一个独特的环境，通过在分析基因组数据，建模信号通路和转录调节网络以及胚胎脑肿瘤中的临床专业知识方面结合优势。我们将共同生成和合并所有类型的转录，基因组和表观基因组数据，提取与生物学相关的网络模型，并实验验证新的药物靶标。