核膜蛋白LEM4调控有丝分裂和染色体稳定性的功能和机制研究

前期发现LEM4能激活或增强CyclinD-CDK4复合物活性，促进细胞周期G1/S期转化，导致雌激素受体阳性乳腺癌产生他莫昔芬治疗抵抗。LEM4对核膜装配调控起关键作用，预实验结果表明LEM4失调造成核膜稳态丧失、中心体扩增和染色体分离异常。但LEM4在有丝分裂和染色体稳定性调控中的功能和作用机制未知。本项目拟利用已建立的LEM4敲除及敲入细胞模型和小鼠模型，研究LEM4在中心体发生、核膜动态变化和有丝分裂期染色体行为等细胞生物学过程中的功能；挖掘LEM4与有丝分裂相关激酶的调控关系，重点分析LEM4与CDK1互作、LEM4与Aurora-PLK1信号级联模块互作的机制及其功能；揭示LEM4在中心体复制起始和成熟、有丝分裂启动和纺锤体双极形成、染色体双极定向和分离中的作用机制。项目的实施有助于理解核膜缺陷导致基因组失稳的机制，有助于肿瘤的精准干预。

LEM4 plays a key role in maintaining nuclear envelope (NE) integrity during interphase and enabling NE reassembly during mitosis. Our previous study showed how LEM4 proteins orchestrate the major group of molecules controlling the cyclin D-CDK4-Rb axis activated during the G1/S phase transition. In this project, we will study the role of LEM4 in maintenance of genomic stability during mitosis: (1) To determine how the LEM4 dysregulation would cause the centrosome amplification, the damage of the NE dynamics and the chromosome missegregation during mitosis. (2) To characterize the functions of the interaction of LEM4 proteins with mitotic kinases, such as CDK1, Aurora-A, Aurora-B and PLK1. (3) To discover the effect of LEM4 dysregulation on lamins and BAF subcellular localization. This study could potentially address the novel mechanism which enables genomic stability during mitosis. And the establishment of LEM4 biological function could provide ideas to understand tumorigenesis or ageing.