衰老进程中RIG-I信号通路激活机制的研究

Persistent inflammatory response was obviously present in senescent cells. Previously, we found that chronic inflammation in the aging process was mediated by retinoic acid inducible gene-I ( RIG-I ) signaling pathway. However, there was nothing to know about the activation of RIG-I in non-infectious condition. In the study, we constructed the in vitro detection model of activated RIG-I, and screened the sustance in senescent cells that could activated RIG-I and researched the mechanism of activation. The purpose of this study is to find the mechanism of RIG-I activation in the aging process, which helps to clarify how chronic inflammation promotes aging, thereby delaying the occurrence and development of a variety of aging-related diseases.

衰老细胞伴随持续性的炎症反应。我们前期研究发现维甲酸诱导基因-I（retinoic acid inducible gene-I, RIG-I）信号通路介导了衰老的炎症。但是至今学界对RIG-I信号通路在非感染条件下是如何被激活的一无所知。我们将从建立体外激活RIG-I的技术着手，并基于这样一种技术，寻找和筛选RIG-I的激活物，同时研究这种激活机制。这一研究将有助于阐明衰老的炎症机制，也将为各种衰老疾病的防治和治疗提供新的依据。

衰老是一个炎症失衡的过程，我们发现在诱导性衰老过程中促炎蛋白的RIG-I表达逐渐上调，而抑炎蛋白klotho的表达则逐渐下调，出现炎症失衡。启动子分析发现它们存在共同的转录因子可能结合位点。进一步研究发现诱导性衰老过程中，转录因子IRF1表达逐渐上调，且IRF1在诱导性衰老过程中具有双重作用，一方面上调RIG-I，另一方面则下调Klotho，最终导致慢性炎症失衡。同时，我们通过异位表达高迁移率族AT Hook蛋白2（HMGA2）在WI38细胞中构建了一个SAHF装配的衰老模型。在该模型中，我们鉴定了典型的衰老特征，包括升高的SA-β-半乳糖苷酶染色和Wnt途径的下调。然而，仅仅GSK3β活性，而不是下游靶基因的活性，对于Wnt通路的下调后的HMGA2诱导的SAHF形成是至关重要的。本课题的研究对于治疗衰老相关疾病提供了新的靶点，也提出了新的治疗思路。