过表达Axl调控cGAS-STING抑制衰老相关分泌表型（SASP）延缓血管衰老的作用及机制

Aging of the vasculature plays a central role in development of cardiovascular diseases in the elderly. The cGAS-STING promotes the senescence-associated secretory phenotype (SASP) by recognizing the cytoplasmic chromatin fragments of senescence cells which would form microenvironment of senescent tissue and accelerate the aging of tissues and organs. Nevertheless, there are few key factors which could effectively inhibit the activation of cGAS-STING in vasculature. Axl is widely expressed in vascular endothelial cells and smooth muscle cells. Our previous studies indicated that overexpression of Axl could protect endothelial function and inhibited SASP factors in senescent endothelium which express less Axl receptor. However, the specific mechanisms of Axl overexpression mediated cGAS-STING inhibition in vascular aging are still unknown. Based on the knowledge of our preliminary studies, with models of genetically modified aging mice, senescent AECs and ASMCs in vitro, with RNA interference, PI3K inhibitor, using cell biology, molecular biology, immunology and imaging methods, we are trying to elucidate the molecular mechanisms of overexpression Axl delay vascular aging by inhibit cGAS-STING mediated secretion of SASP factor. This program will provide a new strategy for clinical prevention and treatments of cardiovascular disease in the elderly by anti-vascular senescence from the destroyed sensing of the genome stress.

血管衰老是老年人心血管疾病发生发展的关键关节。cGAS-STING通过识别衰老细胞的胞质染色质片段促进衰老相关分泌表型（SASP），形成衰老组织微环境，加速组织和器官衰老。目前尚缺乏有效抑制血管内cGAS-STING激活的因子。Axl在血管内皮细胞及平滑肌细胞中广泛表达，我们前期研究提示激活Axl能保护血管内皮功能，预实验提示衰老血管内皮细胞Axl表达降低，过表达Axl能抑制SASP因子分泌。过表达Axl能否调控cGAS-STING延缓血管衰老目前尚未见报道。本课题拟在前期研究基础上，构建各年龄代基因修饰小鼠模型，大鼠主动脉内皮细胞和平滑肌细胞复制性衰老模型，使用RNA干扰、信号通路抑制剂为干预条件，运用细胞生物学、分子生物学、免疫及影像学等方法，阐明过表达Axl调控cGAS-STING抑制SASP延缓血管衰老的作用及分子机制，这将为老年心血管疾病的临床防治提供新策略。

老年患者骨质疏松性骨折的发病率已经超过心血管疾病和肿瘤，成为影响老年人生活质量和寿命的重要疾病。cGAS-STING能介导抗肿瘤免疫和细胞衰老，但目前尚没有研究报道cGAS-STING在骨衰老中的作用。在本研究中，我们建立了成骨细胞炎症衰老模型，利用细胞生物学、分子生物学及免疫学技术检测cGAS-STING-NLRP3炎症小体通路激活情况、线粒体自噬激活情况及其可能机制，并观察调控Axl逆转成骨细胞衰老的作用以及对cGAS-STING-NLRP3炎症小体通路激活情况。我们的研究结果发现，cGAS-STING-NLRP3通路在炎症性衰老的成骨细胞中被激活，过表达Axl能抑制cGAS-STING-NLRP3炎症小体通路，下调cGAS-STING信号抑制SASP分泌，过表达Axl保护成骨细胞衰老。同时，我们还发现成骨细胞的炎症性衰老可能有自噬相关分子的参与。本研究首次发现了Axl-cGAS-STING-NLRP3炎症小体通路在骨衰老中的作用，并探讨了其可能机制，这将为临床防治衰老相关骨质疏松提供理论依据和新策略。