去泛素化修饰SIRT7调控血管内皮衰老分子机制研究

SIRT7, one of the members of Sirtuin family, mainly regulates lipid metabolism, mitochondrial homeostasis, and inhibition of stem cell aging. SIRT7 deficient mice show the pre-mature aging phenotype. However, the regulation of SIRT7 in aging is not clear. Our preliminary data showed that USP47 deubiquitinates and stabilizes SIRT7, which in turn regulates SIRT7 related signaling. We will further study the molecular mechanism of SIRT7 deubiquitination in vascular endothelial cell senescence. In addition, we will demonstrate the role of the AMPK-USP47-SIRT7 axis in energy restriction mediated anti-aging effect. Our preliminary data showed the phenotypic and molecular signs of accelerated aging in USP47 knockout mice. We will further study the coordination of USP47 and SIRT7 in the regulation of vascular aging.

SIRT7是Sirtuin家族重要成员，其主要功能为调控脂质代谢，线粒体稳态及抑制干细胞衰老。SIRT7敲除小鼠具有经典早衰表型。但是SIRT7在衰老过程中的调控机制尚不清楚。本项目前期发现SIRT7的去泛素化修饰调控其生物学功能，去泛素酶USP47能去泛素化并稳定SIRT7，并调控其下游信号通路。拟进一步阐明USP47通过SIRT7调控血管内皮细胞衰老分子机制，最终阐明AMPK-USP47-SIRT7信号轴在能量限制拮抗血管内皮衰老中的作用机理。前期发现USP47小鼠具有早衰表型，拟在组织器官水平及小鼠个体水平深入研究USP47-SIRT7协同调控血管及个体衰老生物学功能。

Sirtuin 蛋白是一组具有 NAD+依赖性的组蛋白去乙酰基转移酶，可以通过对多种底物进行去乙酰化作用，从而在机体内参与一系列的生物学活动。 SIRT7是Sirtuin家族重要成员，其主要功能为调控脂质代谢，线粒体稳态及抑制干细胞衰老, 但是SIRT7在衰老过程中的调控机制尚不清楚。本项目阐明去泛素酶USP47通过去泛素化SIRT7调控其生物学功能，进一步阐明USP47通过SIRT7调控血管内皮细胞衰老分子机制，最终阐明AMPK-USP47-SIRT7信号轴在能量限制拮抗血管内皮衰老中的作用机理。通过建立USP47敲除小鼠，在组织器官水平及小鼠个体水平阐明USP47调控血管及个体衰老生物学功能。