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：
8277793
负责人：
Kristina Ann Cole
金额：
$ 16.18万
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/8277793
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 Instruction 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 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 neuroblastoma cell novel pre-clinical research study treatment strategy tumor tumorigenesis

项目摘要

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 (See instructions): 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.

神经母细胞瘤仍然是儿童中最致命的癌症之一，我们的能力正达到一个平台期通过增加治疗强度来提高生存率。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。尽管对复发基因组的了解已经有三十年了神经母细胞瘤中的异常，除了神经母细胞瘤癌基因 MYCN 之外，这些基因的靶标畸变仍然未知，也没有真正的神经母细胞瘤肿瘤抑制基因确定。一类新的调节性非编码 RNA 的发现，称为 microRNA (miRNA) 有吸引力的候选神经母细胞瘤癌基因和肿瘤抑制基因，因为它们在正常细胞中的作用胚胎发育和癌症。我们假设致癌和抑癌 microRNA （oncomirs）有助于神经母细胞瘤的肿瘤发生。该提案旨在通过 1) 识别来测试这一点通过综合基因组方法研究神经母细胞瘤癌瘤，2) 表征肿瘤抑制因子 miR-34 家族（和其他已识别的癌基因）在神经母细胞瘤中的机制以及 3) 证明 miR-34a替代物的体内临床前治疗效果。这项工作的发现将在癌症生物学中具有更广泛的应用，因为在神经母细胞瘤中发现的许多基因组改变是也发现于其他儿童和成人实体瘤中。该提案制定了为期 5 年的研究和培训计划，最终目标是实现校长的过渡一名由 R01 资助的独立医师科学家的调查员。她的导师和顾问都是该领域的领导者神经母细胞瘤、转化基因组学和基因治疗领域。她将利用充足的费城儿童医院和费城大学的环境资源宾夕法尼亚州。相关性（参见说明）：大多数患有神经母细胞瘤的儿童患有高风险疾病，这些患者的生存率仍然较低尽管加强了细胞毒治疗，但仍超过 40%。治愈率的进步将来自于全新的治疗方法基于恶性神经母细胞中存在的基本改变的治疗策略。我们建议通过综合基因组学方法鉴定致癌和抑癌 miRNA 进一步表征它们，以转化为治疗高危神经母细胞瘤儿童的新疗法。