腹主动脉瘤（abdominal aortic aneurysm，AAA）以中膜弹力层破坏为特征病理改变，血管破裂是主要死因；危害极大但有效药物防治靶点匮乏。申请人前期意外发现TRPM7通道介导少量锌离子（Zn2+）内流，但显著增强金属基质蛋白酶（MMP）活性与表达。受此启发且由于转运体是Zn2+跨膜转运的核心方式，本研究因此聚焦Zn2+转运体，首次发现AAA时：①血管平滑肌锌内流增强与ZIP6转运功能增强密切相关；②有意思的是，ZIP6功能增强与表达变化无关，而ZIP6同源二聚体化及AMPKα2介导的磷酸化可能是关键原因。因此假设：AAA时ZIP6介导锌内流增强，活化MMP或促进表达，降解中膜基质破坏结构。拟利用ZIP6基因敲除小鼠与病人标本多手段探讨Zn2+跨膜转运异常在AAA发病中的作用和机制。本研究将从“Zn2+失稳态”新角度为AAA发病机制提供新见解，评估靶向ZIP6的治疗学意义。

Abdominal aortic aneurysm (AAA) is characterized by degradation of medial elastic layer with aortic rupture being the major cause of death. Unfortunately, no efficient drug therapy is presently available for this grave vascular disease. Surprisingly, we have previously shown that TRPM7 channel-mediated slight Zn2+ influx significantly enhanced the activation and transcription of extracellular matrix-degrading enzyme --- MMP (matrix metalloproteinase). We were inspired to embark on investigating Zn2+ transporters in AAA given that it is Zn2+ transporter protein that plays central roles in Zn2+ transmembrane transport. Our preliminary data showed that during AAA: 1) increased Zn2+ entry in vascular smooth muscle was due to enhanced ZIP6 function; 2) interestingly, the increase in ZIP6 function was not attributable to elevated ZIP6 expression, but rather was associated with ZIP6 homodimerization and AMPK α2-mediated phosphorylation. We thus hypothesized that ZIP6-mediated Zn2+ influx activated MMP and enhanced its expression through Zn2+-sensitive transcription factor --- MTF1, consequently degrading medial extracellular matrix and compromising medial integrity. ZIP6 knockout mice and AAA patient samples will be employed to explore the role of aberrant Zn2+ transport in the pathogenesis of AAA and dissect the underlying mechanisms. This study will provide novel insights into the pathogenesis of AAA and evaluate if ZIP6 could be therapeutically exploited to treat AAA.