Elucidating the regulation of signal transduction by polyadenylation

令人惊讶的发现是，RNA多腺化位于PI3K/mTOR途径激活的上游，这表明该途径中要么有多腺化因子的作用，要么有一种未知的多腺化RNA参与了它的调节。无论是哪种发现都将是根本性的创新，并有可能导致新的抗炎或抗癌药物的问世。在本项目中，您将使用细胞系的遗传操作，包括siRNA导入、CRISPR-Cas9敲除和基因重组以及野生型和突变蛋白的过度表达，以表征通过多聚腺苷作用调节信号转导的途径。您将准备用于蛋白质组学和RNAseq分析的样本，并使用生物信息学分析来解释这些全基因组数据。这项工作将有助于聚腺苷酸化抑制剂作为药物的开发。事实上，多聚腺苷化抑制剂虫草素在治疗小鼠乳腺癌方面显示出了希望。

The surprising finding that RNA polyadenylation is upstream of the activation of the PI3K/mTOR pathway suggests that there either is a role for polyadenyation factors in this pathway, or there is an unknown polyadenylated RNA involved in its regulation. Either finding would be fundamentally novel and potentially lead to new anti-inflammatory or anti-cancer drugs. In this project you will use genetic manipulation of cell lines, including siRNA transfection, CRISPR-Cas9 knockout and recombination of genes and overexpression of wild type and mutant proteins to characterise the pathways involved in the regulation of signal transduction by polyadenylation. You will prepare samples for proteomics and RNAseq analysis and use bioinformatics analysis to interpret these genome-wide data. This work will contribute to the development of polyadenylation inhibitors as medicines. Indeed, the polyadenylation inhibitor cordycepin is showing promise in the treatment of breast cancer in mice.