多基因协同诱导的神经内分泌肺癌小鼠遗传模型建立

我们发现，MEN1基因与Kras之间的负反馈调控网络是神经内分泌型肺癌（P-NET）发病的关键节点，Kras突变是P-NET发病的驱动因素，而MEN1调控的染色质重塑等表观遗传调控机制则决定肺癌细胞的神经内分泌分化命运。MEN1基因敲除联合Kras突变可诱导P-NET动物模型，然而该模型在多大程度上模拟人类P-NET有待进一步探讨，肿瘤生物学特性、病理分型等需要深入鉴定。本研究围绕P-NET动物模型建立这一科学问题，通过肺特异性启动子导入及遗传调控方式优化等策略，开展小鼠P-NET遗传模型的优化及标准化、模型分析方法建立、治疗方案优化等研究；鉴定以上模型与人类同类型肺癌在分子标志物、病理组织学分型、疾病发病进程等方面的相似度，建立这一类肺癌评估临床前数据库；深入阐明P-NET发病的表观遗传学机制。有望为P-NET的分子诊断、疾病风险预警及药物筛选提供基因型及表型明确的新型动物疾病模型。

We found that the negative feedback loop in the regulatory network between the tumor suppression gene MEN1 and protooncogene K-ras is essential for the onset of pulmonary neuroendocrine tumor (P-NET). The activation of K-ras drives the pathogenic progression of P-NET, while MEN1-mediated epigenetic regulatory mechanisms determine the final fate of lung adenocarcinoma cells with neuroendocrine differentiation. MEN1 knockout mice bearing K-ras mutations develop P-NET. However, to what extent that this mouse model could represent human P-NET remains to be further explored. The biological characteristics and histological type of these murine tumors need to be further identified. Here we focus on the establishment and characterization of P-NET animal model by utilizing lung specific promoter and optimize genetic regulation strategies. A series of experiments will be carried out, including the optimization and standardization of P-NET mouse model, the establishment of relevant analytical methods and the optimization of the therapeutic treatment etc. The aim of this study is to identify the following factors co-shared between the mouse model and human P-NET, including the molecular bio-markers, histological type, disease progression and so on. We will build up the preclinical assessment database for P-NET and elucidate the underlying epigenetic mechanism of P-NET. Our work will potentially provide a new animal disease model with defined genotype and phenotype, which may benefit the molecular diagnostics, disease risk assessment and drug screening of P-NET.