TR3介导线粒体自噬抑制肿瘤放疗导致的动脉粥样硬化的机制研究

放疗是治疗肿瘤不可缺少的手段。肿瘤患者在接受放疗时，放射线常难以避免的辐照到周围大动脉，从而诱导粥样硬化性心血管病发生。然而，放射线诱导的动脉粥样硬化比自然演化的更迅速、更难治疗，且目前尚无有效方法在保证肿瘤放疗疗效的同时，预防该并发症发生。我们前期发现，放射线诱导TR3表达增加并发生线粒体转位，伴随线粒体自噬水平上调; TR3敲除加速放射线导致的ApoE-/-小鼠动脉粥样硬化进展；TR3正向调控自噬；抑制线粒体自噬加剧放射线诱导的NLRP3炎症。此外，多项研究报道TR3可通过多种途径抑制肿瘤生长。本项目拟在前期工作基础上，以TR3介导的线粒体自噬与NLRP3炎症的关系为主线，深入研究TR3促进线粒体自噬的分子机制，探讨以TR3为靶点正向调控线粒体自噬来逆转NLRP3炎症的可能，以期为防治肿瘤放疗导致的动脉粥样硬化提供新的思路。

When cancer patients receive radiotherapy, it is inevitably involved exposure to surrounding aorta, which might induce cardiovascular disease. However, radiation-induced atherosclerosis(RIA) progresses more rapid and is more difficult to treat than those natural evolution, and its mechanism is not fully understood, and there is no effective way to prevent RIA while ensuring the efficacy of cancer radiotherapy. In our preliminary work, we found that ionizing radiation induced upregulation and mitochondrial translocation of TR3 in macrophages, accompanied with increased level of mitophagy. TR3 deficiency accelerated radiation-induced atherosclerosis in ApoE-/- mice. Next, we found that TR3 promoted autophagy and mitophagy was shown to inhibit radiation-induced NLRP3-mediated inflammatory responses. Moreover, many studies have reported that TR3 can inhibit tumor growth by multiple pathways. Based on our preliminary studies, we will focus on the relationship between TR3-mediated mitophagy and NLRP3-mediated inflammation in this present project. And we aim to reveal the exact molecular mechanism underlying how TR3 regulates mitochondrial autophagy. Furthermore, we strive to explore the possibility of targeting TR3 to enhance mitophagy to reverse NLRP3 inflammation. The overall purpose of this project is to provide new ideas for the prevention of RIA.