Translational Genomics of MicroRNAs in Neuroblastoma

神经母细胞瘤中 MicroRNA 的转化基因组学

基本信息

批准号：
7570880
负责人：
Kristina Ann Cole
金额：
$ 15.43万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7570880
关键词：
1p36 Accounting Adult Apoptosis Cancer Biology Cell Cycle Arrest Cell Line Cessation of life Child Childhood Chromosome abnormality Clinical Code Cytotoxic Chemotherapy DNA copy number Development Disease Embryonic Development Environment Epigenetic Process Evaluation Family Frequencies Functional RNA Funding Future Gene Targeting Genes Genetic Transcription Genome Genomics Goals Human In Vitro Knowledge Lipids MYCN gene Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Maps Mentors Messenger RNA Methods MicroRNAs Modeling Modification Monitor Morbidity - disease rate Mutation Neuroblastoma Oncogenes Oncogenic Outcome Patients Pediatric Hospitals Pennsylvania Phenotype Philadelphia Physicians Pre-Clinical Model Primary Neoplasm Principal Investigator Progression-Free Survivals Proteins Proteomics Recurrence Research Personnel Research Training Resources Role Sampling Scientist Solid Neoplasm Specificity Suppressor Genes Surveys Survival Rate Testing Time Training Programs Translations Treatment Efficacy Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Volume Universities Work Xenograft procedure aggressive therapy base expectation gene therapy high risk improved in vivo nanoparticle neuroblast novel pre-clinical research study treatment strategy tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma remains one of the deadliest cancers in children and we are reaching a plateau in our ability to improve survival with increasing intensity of therapy. Thus, future treatment strategies must rationally exploit known tumor specific alterations. Despite thirty years of knowledge of recurrent genomic abnormalities in neuroblastoma, other than the neuroblastoma oncogene MYCN, the gene targets of these aberrations has remained unknown, and no bona-fide neuroblastoma tumor suppressor genes have been identified. The discovery of a new class of regulatory non coding RNAs called microRNAs (miRNAs) are attractive candidate neuroblastoma oncogenes and tumor suppressor genes because of their role in normal embryonic development and in cancer. We hypothesize that oncogenic and tumor suppressor microRNAs (oncomirs) contribute to neuroblastoma tumorigenesis. This proposal seeks to test this by 1) Identifying neuroblastoma oncomirs through an integrative genomic approach; 2) Characterizing the tumor suppressor mechanism of the miR-34 family (and other identified oncomirs) in neuroblastoma; and 3) Demonstrating preclinical therapeutic efficacy of miR-34a replacement in vivo. The discoveries made from this work will have broader application to cancer biology as many of the genomic alterations found in neuroblastoma are also found in other pediatric and adult solid tumors. This proposal lays out a 5-year research and training program with the ultimate goal to transition the principal investigator to an independent R01-funded physician-scientist. Her mentors and advisors are leaders in the field of neuroblastoma, translational genomics and gene therapy. She will take advantage of the ample resources of her environment, both at the Children's Hospital of Philadelphia and at the University of Pennsylvania. RELEVANCE: Most children with neuroblastoma have high risk disease and survival rates for these patients remains less than 40%, despite intensification of cytotoxic therapy. Advances in cure rates will result from radically new treatment strategies based on the fundamental alterations present in the malignant neuroblast. We propose to identify oncogenic and tumor suppressor miRNAs through an integrative genomics approach and to further characterize them for translation into novel therapies for children with high risk neuroblastoma.

描述（由申请人提供）：神经母细胞瘤仍然是儿童中最致命的癌症之一，随着治疗强度的增加，我们提高生存率的能力正达到一个平台期。因此，未来的治疗策略必须合理利用已知的肿瘤特异性改变。尽管对神经母细胞瘤中反复出现的基因组异常已有三十年的了解，但除了神经母细胞瘤癌基因 MYCN 之外，这些畸变的基因靶点仍然未知，并且尚未鉴定出真正的神经母细胞瘤抑癌基因。一类新的调节性非编码 RNA 的发现，称为 microRNA (miRNA)，由于它们在正常胚胎发育和癌症中的作用，因此成为有吸引力的候选神经母细胞瘤癌基因和肿瘤抑制基因。我们假设致癌和抑癌 microRNA (oncomirs) 有助于神经母细胞瘤的发生。该提案旨在通过以下方式对此进行测试：1）通过综合基因组方法识别神经母细胞瘤原瘤； 2) 表征神经母细胞瘤中 miR-34 家族（和其他已识别的癌基因）的肿瘤抑制机制； 3) 证明 miR-34a 替代物的体内临床前治疗功效。这项工作的发现将在癌症生物学中有更广泛的应用，因为在神经母细胞瘤中发现的许多基因组改变也在其他儿科和成人实体瘤中发现。该提案制定了一项为期 5 年的研究和培训计划，最终目标是将主要研究者转变为由 R01 资助的独立医师科学家。她的导师和顾问是神经母细胞瘤、转化基因组学和基因治疗领域的领导者。她将利用费城儿童医院和宾夕法尼亚大学丰富的环境资源。相关性：大多数神经母细胞瘤儿童患有高风险疾病，尽管加强了细胞毒治疗，这些患者的生存率仍低于 40%。基于恶性神经母细胞中存在的基本改变的全新治疗策略将导致治愈率的进步。我们建议通过综合基因组学方法鉴定致癌和肿瘤抑制 miRNA，并进一步表征它们，以便转化为治疗高危神经母细胞瘤儿童的新疗法。