调控动脉粥样硬化斑块稳定性的新靶点： AMPK/mTORC1/ULK1/2信号通路介导的适度自噬

Atherosclerotic plaque destabilization and rupture directly result in the incidence of acute cardiovascular events, and autophagy inside plaque is one of the major factors influencing plaque stability. Previous research of applicant revealed that low dose of autophagy inducer everolimus can increase plaque stanility and inhibit its development in the early stage of atherosclerosis. However,the question that how to induce moderate autophagy and related molecular mechanisms is still not elaborated clearly. Therefore, the purpose of this research is to discover dynamic variation rule of autophagy level inside plaque during different stages of atheroslerosis as well as the relation between autophagy level and plaque stability with immunohistochemical and fluorescence imaging methods. Then, to further investigate that AMPK/mTORC1/ULK1/2 signaling pathway plays important roles in regulating moderate autophagy and seeking more promising molecular targets for dual-directional regulation of autophagy and improvement of plaque stability through molecular biology techniques. This study aims at investigating that moderate autophagy regulate occurrence and development of atherosclerosis, revealing novel related cellular regulatory network and providing new ideas and effective intervention targets for the whole precaution and treatment of atherosclerosis.

动脉粥样硬化斑块的失稳定和破裂将直接导致急性心血管事件的发生，而斑块内部细胞的自噬程度是影响斑块稳定性的重要因素之一。申请者在前期研究中证实，在动脉粥样硬化早期，给予低剂量自噬诱导剂everolimus(mTOR inhibitor)的干预可增加斑块的稳定性，抑制其进展。然而，如何在动脉粥样硬化发展的全程诱导适度自噬及其相关的分子机制远未阐明。因此，本研究拟通过免疫组化和荧光成像等技术，揭示在斑块的早期和晚期，内部细胞自噬水平的变化，以及与斑块稳定性之间的关系；同时通过分子生物学技术阐明AMPK/mTORC1/ULK1/2在调控自噬程度中发挥的关键作用。 随后，进一步利用对关键分子靶点的干预实现对自噬的双向调控，增加斑块的稳定性。该研究旨在探讨适度自噬在调控动脉粥样硬化发生发展中的重要作用，揭示新的关键分子调控靶点, 为全程防治动脉粥样硬化提供新的思路和有效的干预策略。

动脉粥样硬化斑块的失稳定和破裂将直接导致急性心血管事件的发生，而斑块内部细胞的自噬程度是影响斑块稳定性的重要因素之一。然而，如何在动脉粥样硬化发展的全程诱导适度自噬及其相关的分子机制远未阐明。本研究通过免疫组化和荧光成像等技术揭示与早期斑块相比，中晚期的斑块中细胞（包括平滑肌细胞和巨噬细胞）自噬水平降低，细胞衰老程度增加。同时基于分子影像技术利用PF1-Cy5.5-DMSA-Fe3O4-NPs 和 OPN- Cy5.5-DMSA-Fe3O4-NPs分子探针发现，斑块进展中profilin-1和osteopontin表达增加，与斑块的进展和易损性增加密切相关；给予低浓度的rapamycin可诱导斑块内细胞的适度自噬，降低细胞的衰老水平，抑制斑块的进展，进一步通过分子生物学技术阐明AMPK/mTORC1/ULK1/2在调控自噬程度中发挥的关键作用。 利用对关键分子靶点的干预可实现对自噬的双向调控，增加斑块的稳定性。该研究探讨适度自噬在调控动脉粥样硬化发生发展中的重要作用，揭示新的关键分子调控靶点, 为全程防治动脉粥样硬化提供新的思路和有效的干预策略。