在DNA损伤等胁迫条件下，细胞以被动方式进入衰老状态并长期分泌大量可溶因子，深刻改变周围环境、成为引发多种疾病的诱因，这一特征被称为衰老相关分泌表型(SASP)。与SASP发生发展有关的胞内蛋白与核内分子，学界已有陆续报道。衰老细胞持续性DDR信号的建立是SASP形成的基础，然而其相关分子机制至今不明。我们近期发现临床常规放化疗等处理方式造成的DNA损伤使得成纤维细胞中锌指蛋白Zscan4表达显著上调，并可能在SASP发生发展的过程中发挥重要作用。我们从前期研究中凝练问题，提出有关Zscan4同SASP密切关联的科学假说。以成纤维细胞为研究模型，我们阐释Zscan4参与修复端粒DNA损伤过程中的正向反馈信号通路，揭示与SASP相关的新型靶标并探讨对其进行特异性控制的可行性。本项目将为深入洞悉SASP发生发展的生物学机制，开创针对细胞衰老及其相关疾病的靶向策略，提供重要科学线索与理论依据。

Under DNA damage and other stress conditions, cells enter senescence passively and secrete numerous soluble factors that profoundly alter the surrounding microenvironment and induce multiple pathologies, such a cellular property is termed senescence-associated secretory phenotype (SASP). So far, there are several studies documenting the cytoplasmic molecules and nuclear factors that are functionally linked with SASP development. However, a thorough understanding of the persistent DNA damage signaling that triggers cellular senescence and the SASP as a critical prerequisite, is still lacking. Our recent data indicated that DNA damage generated by chemotherapy and radiation, the mainstay of current anticancer regimens, can significantly upregulate the expression of Zscan4 in human fibroblasts. Preliminary assays suggest that Zscan4 is likely implicated in SASP development upon genotoxic treatments, whereby it plays a key role in promoting such a senescence-associated feature. We raise a series of scientific questions based on previous findings and propose a central hypothesis regarding the correlation between Zscan4 and the SASP. Taking advantage of the fibroblast cells as an optimized model for senescence biology studies, we aim to elucidate the positive feedback loop that is formed by Zscan4-involved telomeric DNA repair and genomic maintenance activities, and uncover novel therapeutic targets associated with SASP progression. Our project will provide insightful clues that allow to appreciate and assess biological mechanisms underlying SASP development, and open new avenues to design advanced targeting strategies for cellular senescence thereby preventing aging-related pathologies.