GATA4对髓核细胞衰老及衰老相关表型的调控作用及机制

Cell senescence and senescence associated secretory phenotype (SASP) play an important role in intervertebral disc degeneration. The regulation mechanism of cell senescence and SASP in nucleus pulposus (NP) cells has not been fully elucidated. A recent study identified GATA4 as a new regulator of the SASP and senescence. However, whether GATA4 controls the SASP and senescence in NP cells is.unknown. Our previous studies found that the expression of GATA4 in NP of old rats significantly increased than that of young rats, and the expression of GATA4 in H2O2-induced senescent NP cells also increased than that of normal NP cells. These results suggested that GATA4 may play a role in senescence of NP cells. In this study, the expression pattern of GATA4 in NP cells of different senescent types will be studied. Then, gain- and loss-of-function experiments will be performed to investigate the relationships between GATA4 and the SASP or senescence. Finally, the mechanisms by which GATA4 regulates the SASP and senescence in NP cells will be explored. Our study will for the first time comfirm the viewpoint that GATA4 is critical for the SASP and senescence in NP cells. By identifying the key element in the regulatory network controlling the SASP and senescence of NP cells, our study will also explore the feasibility of modulating the GATA4 signaling for IVD regeneration.

细胞衰老及衰老相关分泌表型（SASP）在椎间盘退变过程中发挥重要作用，但髓核细胞衰老及SASP的调控机制尚未阐明。最近研究发现GATA4调控IMR90细胞的衰老，在维持其SASP的过程中扮演不可或缺的角色。但GATA4能否调控髓核细胞衰老及SASP未见报道。我们前期发现，高龄大鼠髓核组织中GATA4的表达高于年轻大鼠，而且双氧水诱导过早衰老的髓核细胞中GATA4的表达高于正常髓核细胞，提示GATA4可能在髓核细胞衰老过程中发挥某种作用。因此，本研究首先探明不同衰老类型的髓核细胞中GATA4的表达规律。然后，分别在体外和体内调控GATA4，探讨GATA4对髓核细胞衰老及SASP的影响。最后，探索GATA4调控髓核细胞衰老及SASP的分子作用机制。本研究有望从全新的角度探索髓核细胞衰老及SASP的调控机制，为理解椎间盘退变的细胞学病因及通过干预GATA4防治椎间盘退变打开崭新的思路。