基于下丘脑AQP1介导Drp1/Fis1信号通路调控线粒体功能的肾阳虚实质研究

肾阳虚是常见中医证候，见于多种疾病，常见形寒肢冷、小便清长等症状，前者因能量代谢低下，后者属水液代谢紊乱。研究认为，肾阳虚主要调节点在下丘脑；而下丘脑功能正常有赖于线粒体提供能量，AQP1介导的Drp1/Fis1通路在线粒体能量代谢中起着重要作用。前期研究发现，AQP1敲除后小鼠下丘脑线粒体超微结构异常、HPA轴功能降低、水液代谢紊乱；进一步发现下丘脑线粒体功能失衡、Drp1 mRNA表达显著降低。为此提出假说：下丘脑AQP1-Drp1/Fis1信号通路-线粒体能量代谢-水液代谢平衡失调，是肾阳虚重要发生机制之一。拟建立AQP1-/-小鼠和下丘脑AQP1特异性敲除小鼠，观察其Drp1/Fis1通路、线粒体能量代谢、HPA轴功能、水液代谢等变化，并以温肾药反证，明确AQP1介导的下丘脑线粒体能量代谢失调与肾阳虚水液代谢的关系。为肾阳虚发生机制提供新认识，有助于深入阐释“肾主水”的科学内涵。

Kidney Yang Deficiency (KYD) is a common syndrome in traditional Chinese medicine, which is involved in variety of diseases. It always shows cold body and limbs caused by low energy metabolism and clear urine in large amounts due to the disorder of water metabolism. Date shows that the main regulating point of KYD is in the hypothalamus, while the function of hypothalamus depends on the energy provided by mitochondria. What’s more, the Drp1/Fis1signaling pathway mediated by AQP1 plays an important role in the energy metabolism of mitochondria. In the previous study, after knocking out of AQP1 in the mouse, the abnormality of mitochondria microstructure, down regulation of HPA axis function and the disorder of water metabolism were found in hypothalamus. Then, it’s followed by dysfunction of mitochondria and reduction of Drp1 expression at mRNA level in hypothalamus. Thus we can hypothesize that one of the important mechanism of KYD generation is including this unbalanced relation among AQP1-Drp1/Fis1signaling pathway, mitochondrial energy metabolism and water metabolism in hypothalamus. In this project, we will observe the changes of Drp1/Fis1 signaling pathway, function of mitochondrial energy metabolism, function of HPA axis and changes in water metabolism, which are also proved by kidney warming drugs, to reveal the relation between mitochondrial energy metabolism in hypothalamus and water metabolism in KYD by using AQP1 knock-out mice and AQP1 conditional knock-out in hypothalamus mice. This study could provide a new sight for pathogenesis of KYD, which may help to illuminate the essence of kidney governing water.