脑缺血再灌注损伤是引起缺血性卒中脑损伤的主要原因之一，近期研究显示：独立于坏死和凋亡之外的新型细胞死亡方式：“程序性坏死”参与了脑缺血再灌注损伤的发生，RIPK3蛋白则在程序性坏死启动过程中扮演关键作用，但相关分子通路尚不明了。前期工作显示：泛素E3连接酶CHIP与RIPK3存在相互作用，其能够泛素化RIPK3并介导其通过UPS通路降解，发挥类RIPK3抑制剂作用。基于以上发现，我们推测：在脑缺血再灌注损伤过程中，CHIP蛋白是否也可通过调控RIPK3泛素化过程参与调控程序性坏死？通过外源性小分子药物和基因修饰手段调控CHIP蛋白表达是否可能下调脑缺血再灌注损伤后程序性坏死水平从而起到脑保护作用？本实验拟从分子、细胞、动物多水平探讨CHIP蛋白调控RIPK3介导的程序性坏死参与脑缺血再灌注损伤的分子机制并探寻新的治疗策略，本研究的开展将为缺血性卒中脑保护研究提供新的思路，具有重要意义。

Cerebral ischemia-reperfusion injury is one of the most prevalent causes for brain damage caused by ischemic stroke. Different from necrosis and apoptosis, necroptosis as a novel mode of cell death has been reported to be involved in the neuron damage induced by cerebral ischemia-reperfusion injury, and RIPK3 plays an important role in this molecular pathway. However, the related pathogenesis remains elusive. In our previous work, we identified the interactions between carboxyl terminus of Hsp70-interacting protein (CHIP) and receptor-interacting protein kinase 3 (RIPK3), and CHIP could regulate the ubiquitination of RIPK3 and mediate degradation of RIPK3 via the ubiquitin-proteasome pathway. Based on these findings, we put forward a hypothesis that CHIP may be involved in the RIPK3-mediated necroptosis via regulating the ubiquitination of RIPK3 in the cerebral ischemia-reperfusion injury models. Besides, upregulation of CHIP by small molecular drugs or gene modification may attenuate necroptosis in models of cerebral ischemia-reperfusion injury. In this study, we will investigate the pathogenesis of CHIP involved in the RIPK3-mediated necroptosis in the cerebral ischemia-reperfusion injury by the cell models and cerebral ischemia-reperfusion/CHIP transgenic mice models, and find the potential therapeutic strategy of cerebral ischemia-reperfusion injury. Based on the solid previous work in accordance with the scientific hypothesis and advanced experiment methods, this study is expected to provide novel strategies for the neuroprotective therapy in ischemic.