核膜蛋白Lamin A的缺陷破坏细胞核纤层的完整性，导致核骨架异常，进而诱发疾病，如HGPS早老症。我们前期研究发现HGPS细胞核内亚结构PML NBs由经典的圆点状变成线性，且证明该异常线性结构与细胞衰老密切关联。实验证据支持线性PML NBs可作为HGPS细胞衰老的新标志物。但线性PML NBs形成的具体分子机制及PML在早老症中的作用机制仍不清楚。本项目延续前期工作进一步深入开展研究：首先，通过制备PML2特异性抗体，结合免疫荧光、电镜及生化分析等阐明线性PML NBs形成的分子机制；其次，通过干预PML的表达探讨其在HGPS细胞及Zmpste24−/−早老小鼠模型中的功能作用。最后，通过解析与PML NBs结合作用的基因群在早老症中的相关功能，以及PML对早老细胞中DNA损伤修复的调控作用等途径，阐明PML在早老症中的作用机制。

The deficiency of nuclear membrane protein Lamin A disrupts nuclear lamina integrity and causes nuclear structure abnormalities, leading to human diseases, such as Hutchinson-Gilford progeria syndrome (HGPS). Our previous study uncovered that the classical dot-like PML nuclear bodies (PML NBs) were reorganized into thread-like structures in HGPS patient fibroblasts and their presence was associated with senescence. Our previous data support that the thread-like PML NBs could be a novel, morphological and functional biomarker of senescence. However, the mechanisms of thread-like PML NBs formation and the role of PML in progeria remain unclear. In this proposal, we first try to clarify the mechanisms of the thread-like PML NBs formation by using PML2-sepecific antibodies together with immunofluorescence and electron microscopy as well as biochemical analysis. Next, we examine the roles of PML in progeria via interfering the PML expression in the HGPS patient fibroblasts and Zmpste24−/− progeria mice. Finally, we try to clarify the molecular mechanisms of PML in progeria via analyzing the functions of identified PML NBs-associated genes and the roles of PML in regulating DNA repair.