Dissect regulation of RNA translation in human cancers

项目摘要 研究表明，RNA翻译在致癌转化过程中起着重要的调控作用， 癌症进展和转移。靶向RNA翻译用于癌症治疗具有巨大的潜力。 然而，在全基因组基础上的肿瘤发生过程中的翻译调控仍然在很大程度上未被探索， 目前大多数癌症研究仍然集中在转录组上。在这里，我建议使用一个综合实验 和计算基因组学的方法来系统地剖析RNA翻译的调控和 翻译因子在人类癌症中的功能作用。目的1将研究mRNA的全基因组调控 在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。的 结果将揭示新的机制和功能的目标，翻译调控潜在的致癌 转化和癌症异质性。目的2将研究翻译因素的功能作用及其在翻译中的作用 在致癌转化过程中的全基因组靶点。这项研究将为靶向治疗提供机制性见解。 用于癌症治疗的翻译因子。目的3将描述RNA翻译和基因共表达的调控。 使用蛋白质组学的人类癌症患者样品中翻译因子的表达网络， 来自癌症基因组图谱（TCGA）数据库的转录组学数据。这一分析将显示， 使用目的1和2中的癌细胞系模型发现的调节机制有助于体内 癌症进展和异质性。总之，拟议的实验将系统地剖析 人类翻译调控和翻译因子的功能作用和全基因组靶点 癌的这一结果将为靶向RNA翻译治疗癌症提供新的机制基础。 虽然我在计算基因组学、癌症生物学和 分子生物学，K99/R 00奖将帮助我发展实验技能，包括实施下一步- 代测序技术和分子生物学技术。这项研究将采取 我的导师凯文博士（Dr. Kevin Struhl在哈佛医学院和Aviv Regev博士在麻省理工学院和哈佛的布罗德研究所）和我的 Dana Farber癌症研究所的Jean Zhao博士。哈佛医学院和布罗德研究所 为我提供了一个良好的培训环境。建议的研究将有助于我的事业 发展成为一名独立的科学研究人员，在癌症系统生物学的前沿工作 并开发新的人类癌症治疗策略。

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.