Dissect regulation of RNA translation in human cancers

项目总结 研究表明，RNA翻译在致癌转化过程中起着重要的调节作用， 癌症的进展和转移。靶向RNA翻译用于癌症治疗具有巨大的潜力。 然而，在全基因组的基础上，在肿瘤发生过程中的翻译调控在很大程度上仍然没有被探索，因为 目前大多数癌症研究仍集中在转录组方面。在这里，我建议使用一个综合实验 和计算基因组学方法，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将研究全基因组范围的mRNA调控 多种癌基因和抑癌基因介导的致癌转化过程中的翻译。这个 研究结果将揭示致癌基因翻译调控的新机制和功能靶点 转化和肿瘤异质性。目标2将研究翻译因素的功能作用和他们的 致癌转化过程中的全基因组靶点。这项研究将为目标确定提供机械性的见解 癌症治疗的翻译因素。目标3将描述RNA翻译和基因协同的调控。 应用蛋白质组学和蛋白质组学方法研究人类癌症患者样本中翻译因子的表达网络 来自癌症基因组图谱(TCGA)数据库的转录组数据。这一分析将表明， 利用AIMS 1和AIMS 2的癌细胞模型发现的调节机制有助于体内 癌症进展和异质性。综上所述，拟议的实验将系统地剖析 翻译调控和翻译因子在人类中的功能作用和全基因组靶点 癌症。这一结果将为肿瘤治疗中靶向RNA翻译提供新的机制基础。 虽然我在计算基因组学、癌症生物学和 分子生物学，K99/R00奖将帮助我培养实验技能，包括实现NEXT- 以世代测序技术和分子生物学技术为基础。这项研究将需要 利用首席调查员、我的导师(凯文博士)的独特和互补的专业知识 哈佛医学院的斯特鲁尔和麻省理工学院和哈佛大学博德研究所的阿维夫·雷格夫博士)和我的 合作者(达纳·法伯癌症研究所的Jean赵博士)。哈佛医学院和博德研究所 为我提供一个特殊的培训环境。拟议中的研究将有助于我的事业 发展成为在癌症系统生物学前沿工作的独立科学研究者 以及为人类癌症开发新的治疗策略。

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.