脑中风是导致全球病人致死和致残的重要原因。我们研究发现TMEM166与脑缺血损伤后的神经损伤密切相关。本研究在TMEM166基因敲除鼠颈动脉狭窄模型的基础上观察其在该过程中的作用并重点探讨其机制。.ApoE-ε4和wnt/β-catenin通路与内膜厚度显著相关，我们的预实验证实颈动脉狭窄患者TMEM166-ApoE-ε4复合物明显增加，wnt/β-catenin通路激活。在小鼠颈动脉狭窄模型中也有类似发现，且上述指标在TMEM166基因敲除鼠，或在给予ApoE-ε4shRNA或wnt特异性抑制剂IWR-1-endo后则明显被抑制，同时管腔狭窄改善；而给予Lv-TMEM166后，wnt/β-catenin通路被激活，管腔狭窄显著。因此我们提出科学假说：TMEM166与ApoE-ε4结合后通过激活并放大wnt/β-catenin信号通路，介导管腔狭窄，最终导致缺血性脑中风发生。

Stroke and its sequelae continue to be a leading cause of disability and mortality worldwide. Despite interventional treatments that significantly decrease the general incidence of stroke, a majority of patients suffer from serious ischemia/reperfusion injury in the process. Our previous study showing TMEM166’s involvement in brain damage following ischemia/reperfusion in rats suggests TMEM166 to be a potential novel therapeutic in human stroke. In this proposal, we will explore the role of TMEM166 after balloon injury with TMEM166 knock-out mice and focus on the possible mechanisms regulated by TMEM166. .ApoE-ε4 and wnt/β-catenin signaling pathway is related with wall thickness of carotid arteries. In our preliminary tests, ApoE-ε4-TMEM166 compound experienced a significance increase and wnt/β-catenin signaling pathway was activated in patients with carotid artery stenosis. In the mouse carotid artery stenosis model, similar results were obtained. Besides, ApoE-ε4 expression and wnt/β-catenin signaling pathway were both inhibited, and the restenosis was significantly improved in the TMEM166 knock-out mice, and when ApoE-ε4shRNA or wnt specific inhibitor IWR-1-endo was administrated. However, wnt/β-catenin signaling pathway was activated and carotid artery stenosis rate increased after Lv-TMEM166 treatment. Thus, we hypothesized that TMEM166 regulates carotid artery stenosis and leads to ischemic stroke through combination with ApoE-ε4 and the subsequent activation of wnt/β-catenin signaling pathway.