多内分泌腺瘤病2型（MEN2）具有显著的临床表型异质性，亟待阐明除RET基因突变外新的分子机制。课题组前期利用外显子捕获及二代测序技术，发现并证实78%的MEN2相关肿瘤细胞存在体细胞RECQL4基因变异。本课题拟以此发现为基础，首先在大样本MEN2相关肿瘤中确认RECQL4基因变异的发生率及其与MEN2临床表型的相关性；进一步，利用siRNA干扰技术分别并同时抑制RECQL4及RET基因在MEN2相关肿瘤细胞株中的表达，分析细胞的增殖、凋亡、侵袭以及核型的变化，并探讨相关分子机制；进而构建裸鼠及双基因knock-in小鼠模型，分析RECQL4基因变异与RET突变协同作用在MEN2相关肿瘤发生发展中的意义,从而最终为MEN2患者提供新的临床评估及治疗靶点。

The clinic heterozygosity of multiple endocrine neoplasia type 2 (MEN2) require exploration of novel molecular mechanisms of MEN2 in addition to germline RET mutation. Our previous studies revealed and confirmed that 78% of MEN2 related tumors carried a somatic RECQL4 variation. The proposed project is to first explore the frequency of this RECQL4 variation in a large sample size of MEN2 related tumors and its correlation with the clinical manifestation; knock down RECQL4 and RET independently and simultaneously in MEN2 cell lines to investigate cell proliferation, apoptosis, invasion and karyotype, as well as molecular mechanisms; establish nude mice model and RECQL4/RET mutation double knock-in mice to observe the tumor development and progression, which might eventually offer a new target for clinical evaluation and drug development.