血管平滑肌细胞特异性自噬在烟酸姜黄素酯抗血管老化中的作用和机制

We have designed and synthesized Curcumin trinicotinate (CurTn) is a new curcumin derivative, Curcumin trinicotinate (CurTn). CurTn was , which has been found to have an anti-vascular aging effect, but its the underlying mechanisms are unknown. Our pPreliminary studies-experiment and molecular docking results showed that CurTn can promote autophagy. It is known that aAutophagy of vascular smooth muscle cells (VSMCs) is associated with can affect cell senescence. We have established a transgenic mouse model withThe VSMCs specific autophagy inhibition in VSMCs through conditional knockout of Atg7 in SMCs (Atg7-/-) and mouse model that we constructed also found the a cause-effect relationship between SMC autophagy inhibition and vascular aging. This project was designed intends to observe investigate the effects of CurTn on vascular aging through three 3different kinds of animal models, and and examine the effects of CurTn on VSMCs autophagy and vascular functions in vivo and in vitro. Our studies using the mouse model with SMC-specific autophagy inhibition will addressThen make explicit whether activation of VSMCs autophagy is the key path mechanism underlying in CurTn anti-vascular aging effect through VSMCs specific autophagy inhibition in mice. Using Through shRNA methodapproach, we will clarify whether CurTn promotes autophagy by inhibiting the PI3K/mTOR signaling pathway and/or promote the activation of TFEB at the molecular level. The project will shed light on clear the anti-vascular aging effect of CurTn and also reveal, clarify the mechanism roles of VSMC-s specific autophagy in anti-vascular aging. Our findings will provide a new drug selection target for treating vascular aging and open a new avenue to , and provide new theoretical basis and intervention target for prevention and treatment of aging-related the development and progression of vascular diseases., and provide new drug selection for treatment of vascular aging.

烟酸姜黄素酯（CurTn）是本课题组新合成的姜黄素衍生物，前期发现具有抗血管老化作用，但其机制不明。预实验及分子对接结果发现CurTn可促进细胞自噬，且血管平滑肌细胞（VSMCs）自噬能影响细胞老化，我们构建的VSMCs特异性自噬抑制（Atg7-/-）小鼠模型也发现了自噬与血管老化的关系。本项目拟采用3种动物衰老模型观察CurTn对血管老化的影响；明确CurTn在体内外对VSMCs自噬和功能的影响；然后通过VSMCs特异性自噬抑制小鼠明确VSMCs自噬是否是CurTn抗血管老化的关键途径；通过shRNA等方法，在分子水平阐明CurTn是否能通过抑制PI3K/mTOR信号通路和/或促TFEB活化发挥促自噬作用。该项目将明确CurTn的抗血管老化作用，阐明VSMCs特异性自噬在CurTn抗血管老化中的作用机制，为防治血管疾病发生和进展提供新的理论依据和干预靶点，为治疗血管老化提供新的药物选择。

本课题组顺利完成科研课题。首先我们新合成了姜黄素衍生物，烟酸姜黄素酯（CurTn），并发现具有抗血管老化作 用，对其机制进行了研究。结果发现CurTn可促进细胞自噬，且血管平滑肌细胞自噬能影响细胞老化。除了小鼠和人血管平滑肌细胞细胞外，我们还在其他多个系统，包括线虫等，进行了研究和探讨。在开展课题的过程中，我们培养了6 名硕士研究生，3名博士研究生。 发表了一系列高质量的科研论文。并与加拿大卡尔加里大Morley D. Hollenberg 和Michael P. Walsh实验室建立了合作关系。