中文摘要
现有诊疗体系不能有效改善大肠癌(CRC)患者预后,遂亟需发现、验证新型特异性敏感性生物标记物并阐明相关靶向药物机制。我们在前期发现“高表达miR-150下调靶基因c-myb并改善CRC患者预后”基础上,首先拟通过临床大样本检测明确miR-150在常见肿瘤中诊断特异性及敏感性,并通过细胞、动物实验明确miR-150对不同肿瘤细胞生长的影响。其次,在前期已有基础上制备两种载体(配体靶向型多肽纳米载体HKP、脂质载体)包裹的miR-150小核苷酸药物并通过基因组学、表观遗传学利用免疫共沉淀、焦磷酸测序等技术厘清miR-150可能使c-myb改变的表观遗传特征,寻找及验证可能影响c-myb表达和功能的分子伴侣(ACF7)及信号通路。最后,构建miR-150及c-myb肠上皮敲除小鼠验证其作用机制。以上发现有助于推动miRNA相关基础研究成果向临床转化,推进CRC个体化精准治疗体系建立。
英文摘要
The existing treatment system could not effectively improve the prognosis of patients with colorectal cancer(CRC), so we need to find and verify new biomarkers with high specificity and high sensitivity and also elucidate the relevant targeted drug mechanism. We have found that "high expression of miR-150 down-regulates target gene c-myb and improves the prognosis of patients with CRC". Based on the finding, first, we plan to elucidate the specificity and sensitivity of miR-150 in the diagnosis of several common tumors through a large sample of clinical detection, and the effect of miR-150 on the growth of different tumor cells was confirmed by cell and animal experiments. Second, miR-150 will be encapsulated with two carriers (ligand-targeted polypeptide nanocarrier HKP and lipid carrier). We will clarify the c-myb changes of genomics and epigenetics, using immunoprecipitation, pyrophosphate sequencing and other technologies. We will also clarify the molecular chaperones(ACF7) and molecular signaling pathways which possibly affect the c-myb’s epigenetic characteristics and expression. Finally, miR-150 and c-myb intestinal epithelial knockout mice will be constructed to verify its mechanism. The above findings help to promote the transformation from miRNA related basic research to clinical application, and promote the development of individualized and precise treatment of CRC.
