RNA甲基化酶METTL3介导的m6A动态修饰的致癌功能和化学干预研究

m6A mRNA动态表观遗传修饰对mRNA加工和翻译以及基因表达具有重要调控作用。METTL3介导m6A修饰异常可以导致重要癌基因表达异常从而促进多种恶性肿瘤生长发展，因此m6A修饰异常是肿瘤治疗的新靶点。然而目前没有体内致癌小鼠模型并且缺乏特异的有效抑制m6A致癌通路的药物。本课题拟建立Mettl3条件性敲除和转基因肺癌小鼠模型，为研究Mettl3体内致癌功能和机理以及抑制m6A致癌通路的药物开发提供重要工具，并将利用体外甲基化高通量 筛选方法和计算机模拟筛选优化方法，筛选开发特异抑制METTL3介导的m6A mRNA修饰的小分子化合物，并利用生化分子生物学方法、细胞生物学和小鼠肿瘤模型研究小分子化合物对m6A 修饰和肿瘤发生发展的调控以及相关机理。研究结果将开发特异抑制m6A修饰的小分子抑制剂，为m6A mRNA动态修饰的化学干预和m6A异常肿瘤的治疗干预提供重要基础。

The dynamic m6A mRNA modification plays essential roles in regulation of mRNA processing, translation and gene expression. In addition, The RNA methyltransferase METTL3 mediated mis-regulation of m6A modification promotes oncogene expression and facilitates cancer growth and progression. However, currently there is no in vivo tumor model avaible and lacks specific and effective drug targeting the m6A oncogenic pathway. In this study we will establish Mettl3 conditional knockout and knockin lung cancer mouse models to study Mettl3's oncogenic function and the underlying molecular mechanisms, and to provide useful tools for the development of small molecule drugs targeting the m6A oncogenic pathway. We will use high-throughput in vitro methylation assay and computer-assisted screening and optimization methods to screen and optimize potential small molecule compounds that can effectively inhibit the METTL3 mediated m6A RNA modification. We will use biochemical assays, cellular models and mouse models to study the functions and molecular mechanisms of small molecule compounds in regulation of m6A modification and oncogenesis. Completion of this project will identify novel small molecule inhibitors of m6A oncogenic pathway, and will provide useful tools for m6A modification intervention and the therapy of m6A mis-regulated cancers.