近期研究表明，细胞衰老尽管是一重要的肿瘤抑制机制，但同时也伴随着具有促肿瘤潜力的炎症反应，这一现象的病理意义和调控机制尚不清楚。在本项目的前期实验中我们发现，一方面，在神经胶质瘤的发生过程中，衰老诱导的炎症通路激活能够在细胞逃逸衰老诱导的细胞周期阻滞后转化为非可控性炎症，并进一步促进神经胶质瘤的发生发展。利用原位转化的动物胶质瘤模型加以转录组分析以及RNAi文库筛选，我们进一步鉴定了包括PHF19，TGFB1以及BMP2在内的、维持衰老逃逸后炎症通路持续激活的关键因子。另一方面，我们发现持续的炎症信号能够使得细胞在获得p53以及p16INK4A通路失活突变前即形成衰老逃逸。由此在本项目中，我们基于衰老诱导的炎症向非可控炎症转化，以及炎症信号协助衰老逃逸两方面对衰老相关炎症调控网络进行探讨，研究结果将完善衰老相关炎症的调控理论，而且能够为未来的靶向衰老相关炎症的肿瘤治疗手段提供潜在的靶点。

Cellular senescence induced by activation of oncogenes or inactivation of tumor suppressors represent a critical tumor suppressive check point during tumorigenesis. Recent evidence has shown that activation of inflammatory signaling, which is tumor-promoting, is associated with cellular senescence. However, the underlying regulatory mechanism and physiological significance of this phenomenon is largely unknown. Evidence from our preliminary studies has shown that in the process of gliomagenesis, cellular senescence-induced inflammatory signaling could lead to unsolving inflammation when cells bypassed cell cycle arrest, eventually promoting to glioma progression. By employing in situ transformation animal model transcriptome analysis and RNAi library screening, we identified a series of transcripts associated with activation of senescence-induced inflammatory pathways. Furthermore, by employing RNAi library screening, we found that PHF19, TGFB1 and BMP2 were essential for a sustained NF-κB activation after senescence evasion. These factors synergistically enhanced expression of a series of NF-κB activating factors identified in our previous reports. On the other hand, we found that persistent stimulation by inflammatory signaling in tumor cells, particularly IL6 induced-STAT3 activation, was key to establishment of a senescence evasion state before cells acquired mutation in p53 and p16INK4A pathways. In the proposed study, by using RNAi screening strategy, we attempt to identify essential factors that mediate this process. Taking together, we will dissect the regulatory circuits of senescence-induced inflammation signaling and address two important questions, namely, how senescence-induced inflammation becomes unresolving and how such persistent activation of inflammatory pathways in tumor cells promotes senescence evasion. It is hoped that the data derived from the research will not only provide new insight in our current understanding of mechanism governing senescence-associated inflammation but also identify potential new targets for anti-glioma therapy.