2207 MicroRNA-based single-cell CRISPR screens to discover microRNA-mRNA networks involved in carboplatin resistance in ovarian and lung cancer

2207 基于 MicroRNA 的单细胞 CRISPR 筛选发现参与卵巢癌和肺癌卡铂耐药性的 microRNA-mRNA 网络

• 批准号: 2752941
• 金额: --
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2752941
• 关键词: 2207; MicroRNA; based; single; cell

Carboplatin is a platinum-based chemotherapy drug in lung and ovarian cancer treatment. Unfortunately, despite improved survival, numerous patients relapse and succumb to the disease because of carboplatin resistance. Therefore a further understanding of the evolutionary processes underlying resistance formation is crucial for developing effective treatments that are able to overcome resistance and cancer relapse. MicroRNAs (miRNAs) are small RNA molecules that repress post-transcriptional gene expression by interacting with the 3'UTR of mRNA targets. It has been shown that microRNAs are often involved in chemotherapy resistance in various cancers by regulating the important transcripts that code for proteins involved in this process. We hypothesize that cellular networks of miRNA-mRNA interactions are involved in carboplatin resistance in lung and ovarian cancer. Initially, to evaluate which miRNA-mRNA interaction confers resistance to carboplatin in lung and ovarian cancers, we will integrate miRNA and RNA sequencing in non-resistant and resistant cancer cell lines. These approaches will discover the miRNAs and potential targets that are dysregulated during chemoresistance. Furthermore, to understand their mechanism of action we will establish the first miRNA-based single-cell CRISPR screen to evaluate how selected carboplatin-resistance miRNA-mRNA networks act in carboplatin resistance at single-cell resolution. Important miRNA-mRNA interaction will be further validated by performing gold-standard biochemical experiments. The Discovery of miRNA-target networks involved in this process will provide new insights into the underlying evolutionary processes and, hence, into the principles of evolution as well as new therapeutic avenues to overcome lung and ovarian cancer relapse.

卡铂是一种用于肺癌和卵巢癌治疗的铂类化疗药物。不幸的是，尽管提高了生存率，但许多患者由于卡铂耐药性而复发并死于疾病。因此，进一步了解耐药性形成的进化过程对于开发能够克服耐药性和癌症复发的有效治疗至关重要。MicroRNA（miRNAs）是一类通过与mRNA靶点的3 'UTR相互作用抑制转录后基因表达的小RNA分子。已经表明，microRNA通常通过调节编码参与该过程的蛋白质的重要转录物而参与各种癌症的化疗抗性。我们推测，miRNA-mRNA相互作用的细胞网络参与了肺癌和卵巢癌的卡铂耐药。最初，为了评估哪种miRNA-mRNA相互作用赋予肺癌和卵巢癌对卡铂的耐药性，我们将在非耐药和耐药癌细胞系中整合miRNA和RNA测序。这些方法将发现在化疗耐药性期间失调的miRNAs和潜在靶点。此外，为了了解它们的作用机制，我们将建立第一个基于miRNA的单细胞CRISPR筛选，以评估选定的卡铂耐药性miRNA-mRNA网络如何在单细胞分辨率下作用于卡铂耐药性。重要的miRNA-mRNA相互作用将通过执行金标准生化实验进一步验证。参与这一过程的miRNA靶网络的发现将为潜在的进化过程提供新的见解，从而为进化原理以及克服肺癌和卵巢癌复发的新治疗途径提供新的见解。