Dissect regulation of RNA translation in human cancers

剖析人类癌症中 RNA 翻译的调控

基本信息

批准号：
9307739
负责人：
Zhe Ji
金额：
$ 9.99万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307739
关键词：
Award Binding Biological Process Breast Cancer Biology Cancer Patient Cancer cell line Dana-Farber Cancer Institute Data Data Set Databases Drug Targeting ERBB2 gene Environment Epidermal Growth Factor Receptor Event FRAP1 gene Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Translation Genomic approach Genomics Human Institutes KRAS2 gene Malignant Neoplasms Mediating Mentors Messenger RNA Modeling Molecular Biology Molecular Biology Techniques Mutate Mutation Neoplasm Metastasis Oncogenes Oncogenic Pathway interactions Play Principal Investigator Production Proteins Proteomics RNA RNA immunoprecipitation sequencing Recruitment Activity Regulation Research Research Personnel Resources Ribosomal RNA Role Sampling Suppressor Genes Systems Biology TP53 gene Technology The Cancer Genome Atlas Training Transcriptional Regulation Translation Initiation Translational Regulation Translations Tumor Suppressor Genes anticancer research base cancer cell cancer heterogeneity cancer therapy career development cell transformation cost effective differential expression experimental study genome-wide in vivo insight medical schools new therapeutic target next generation sequencing novel novel therapeutics ribosome profiling skills transcriptome transcriptome sequencing transcriptomics translation factor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Studies have shown that RNA translation plays important regulatory roles during oncogenic transformation, cancer progression and metastasis. Targeting RNA translation for cancer therapy has enormous potential. However, translational regulation during oncogenesis in the genome-wide basis remains largely unexplored, as most current cancer research still focuses on transcriptome. Here I propose to use an integrated experimental and computational genomics approach to systematically dissect the regulation of RNA translation and the functional roles of translation factors in human cancers. Aim 1 will examine genome-wide regulation of mRNA translation during oncogenic transformation mediated by various oncogenes and tumor suppressor genes. The result will reveal novel mechanisms and functional targets of translational regulation underlying oncogenic transformation and cancer heterogeneity. Aim 2 will study the functional roles of translation factors and their genome-wide targets during oncogenic transformation. The study will provide mechanistic insights for targeting translation factors for cancer therapy. Aim 3 will characterize the regulation of RNA translation and gene co- expression networks of translation factors in human cancer patient samples using proteomics and transcriptomics data from the Cancer Genome Atlas (TCGA) database. This analysis will show how the regulatory mechanisms discovered using the cancer cell line models in Aims 1 and 2 contribute to in vivo cancer progression and heterogeneity. Taken together, the proposed experiments will systematically dissect the functional roles and genome-wide targets of translational regulation and translation factors in human cancers. The results will provide a novel mechanistic basis for targeting RNA translation in cancer therapy. While I have received extensive interdisciplinary training in computational genomics, cancer biology and molecular biology, the K99/R00 award will help me develop experimental skills, including implementing next- generation sequencing technologies based and molecular biology techniques. The research will take advantage of the unique and complementary expertise of the principal investigator, my mentors (Dr. Kevin Struhl at Harvard Medical School and Dr. Aviv Regev at the Broad Institute of MIT and Harvard) and my collaborator (Dr. Jean Zhao at Dana Farber Cancer Institute). Harvard Medical School and the Broad Institute provide me with an exceptional training environment. The proposed research will facilitate my career development to be an independent scientific investigator working at the forefront of cancer systems biology and developing novel therapeutic strategies for human cancers.

项目摘要研究表明，RNA翻译在致癌过程中起着重要的调节作用，癌症进展和转移。针对癌症治疗的RNA翻译具有巨大的潜力。然而，在整个基因组的肿瘤发生过程中的翻译调节仍然在很大程度上没有探索，因为当前大多数癌症研究仍然集中在转录组上。在这里，我建议使用集成的实验和计算基因组学方法以系统地剖析RNA翻译的调节和翻译因子在人类癌症中的功能作用。 AIM 1将检查mRNA的全基因组调节由各种癌基因和肿瘤抑制基因介导的致癌转化过程中的翻译。这结果将揭示基础肿瘤基础调节的新机制和功能靶标转化和癌症异质性。 AIM 2将研究翻译因子及其其功能作用在致癌过程中，全基因组靶标。该研究将提供定位的机械见解癌症治疗的翻译因素。 AIM 3将表征RNA翻译和基因共同的调节使用蛋白质组学和来自癌症基因组图集（TCGA）数据库的转录组学数据。该分析将表明如何使用癌细胞系模型在AIM 1和2中发现的调节机制有助于体内癌症进展和异质性。综上所述，提出的实验将系统剖析人类翻译调节和翻译因子的功能作用和全基因组靶标癌症。结果将为靶向癌症治疗中的RNA翻译提供新的机械基础。尽管我接受了计算基因组学，癌症生物学和分子生物学，K99/R00奖将帮助我发展实验技能，包括实施接下来的基于生成测序技术和分子生物学技术。研究将进行我的导师（凯文博士）的独特和补充专业知识的优势哈佛医学院的Struhl和麻省理工学院和哈佛大学广泛研究所的Aviv Regev博士）和我合作者（Dana Farber癌症研究所的Jean Zhao博士）。哈佛医学院和布罗德学院为我提供出色的培训环境。拟议的研究将促进我的职业生涯发展成为癌症系统生物学最前沿的独立科学研究者并为人类癌症制定新的治疗策略。