RIPK1/RIPK3通路调控炎症消退对糖尿病脑梗死的影响和机制研究

炎症是糖尿病恶化脑梗死结局的主要因素，而特化促消退介质介导的炎症消退是决定炎症结局的关键。我们前期研究发现，糖尿病脑梗死中炎症消退异常，但机制尚不明确。我们的进一步预实验提示糖尿病脑梗死中RIPK1/RIPK3通路信号异常升高，而抑制RIPK1/RIPK3通路可以促进特化促消退介质合成。结合前期工作及文献报道，我们提出假说，糖尿病脑梗死中RIPK1/RIPK3通路激活导致炎症消退异常，其机制可能是通过调控AMPK信号和程序性坏死。本项目将利用糖尿病小鼠造模脑梗死模型，研究RIPK1/RIPK3通路和特化促消退介质在糖尿病脑梗死中的关系；再利用基因干预体外细胞模型和RIPK1/RIPK3基因失活/基因敲除小鼠模型，通过转录组mRNA测序技术及生化分析手段，研究RIPK1/RIPK3通路对特化促消退介质的影响机制。研究成果将为明确炎症消退的上游机制提供新证据，也为治疗糖尿病脑梗死提供新靶点。

Inflammation plays a key role in the diabetes-worsened prognosis of ischemic stroke, and resolution of inflammation determines the consequences of inflammatory processes. We found that resolution of inflammation is alerted in diabetic ischemic stroke, but the intrinsic mechanisms are not clear. Our preliminary results have shown that RIPK1/RIPK3 pathway is activated in diabetic ischemic stroke, and inhibition of RIPK1/RIPK3 pathway enhanced biosynthesis of specialised pro-resolving mediators. Based on our findings and literature knowledge, we hypothesise that the activation of RIPK1/RIPK3 pathway in diabetic ischemic stroke leads to abnormal resolution of inflammation via AMPK signalling and necroptosis. In this project, we will first study the effects of RIPK1/RIPK3 pathway on resolution of inflammation in ischemic stroke mouse models with diabetes. And then, by utilising transcriptome mRNA sequencing and biochemical technologies in genetic modified cellular models and RIPK1/RIPK3 gene-inactivated / gene-knockout mouse models, we will explore the intrinsic mechanisms of how RIPK1/RIPK3 pathway regulates resolution of inflammation. The study will provide novel upstream mechanisms for resolution of inflammation, and indicate new therapeutic targets for diabetic ischemic stroke.