自噬功能受损引起胆固醇逆向转运减少、血管细胞炎症激活和凋亡增加，促进易损斑块形成和进展。调控自噬相关信号通路极有希望为改善斑块稳定性提供新的防治策略。我们前期研究发现，易损斑块巨噬细胞中核受体Nur77及其异源二聚体搭档RXRα表达上调且发生胞浆移位，伴随自噬水平下调；Nur77-/- ApoE-/-小鼠颈动脉斑块稳定性明显改善伴斑块体积缩小，而RXRa特异性配体具有相似的抗动脉粥样硬化作用。本项目拟在前期工作的基础上，以Nur77/RXRa蛋白表达、定位与巨噬细胞自噬受损的关系为主线，深入研究Nur77/RXRa通过激活Bax，增加溶酶体膜通透性和引起溶酶体功能紊乱，导致自噬降解过程受阻，参与易损斑块形成的分子机制，揭示Nur77/RXRa作为调控斑块稳定性药物靶点的分子机理，探讨RXRa特异性配体全身及局部给药对易损斑块的治疗作用，以期拓展稳定斑块、预防急性心脏事件的新思路。

Autophagy dysfunction contributes to abnormalities in cholesterol efflux, hyperinflammatory states, increased apoptosis and defective efferocytosis in lesional macrophages, leading to subsequent development of vulnerable atherosclerotic plaques. Therefore, restoring or enhancing autophagy function might represent a potential therapeutic target to treat atherosclerosis and to improve the stability of atherosclerotic plaques. In our preliminary work, we found that both nuclear receptor Nur77 and its heterodimer partner RXRα are highly expressed and mainly localized in the cytoplasm of macrophages in vulnerable atherosclerotic plaques, accompanied by decreased macrophage autophagy. Moreover, we found that Nur77-/- ApoE-/- mice exhibits smaller and more stable atherosclerotic lesions compared to ApoE-/- control mice. Most importantly, we found that the novel RXRα-specific ligand, K80003, exhibits the same protective effects, which means that K80003 may represent a promising drug to stabilize atherosclerotic plaques. Based on our preliminary studies, we will focus on the relationship between the subcellular localization of Nur77/RXRa and macrophage autophagy dysfunction in this present project. And we aim to reveal the exact molecular mechanism underlying how Nur77/RXRa activates Bax and triggers Bax-induced lysosomal membrane permeabilization, resulting in lysosomal dysfunction and autophagy dysfunction, which leads to subsequent development of vulnerable atherosclerotic plaques. Furthermore, we strive to elucidate the mechanisms of targeting Nur77/RXRa as the therapeutic strategy for stabilizing advanced atherosclerotic lesions and to fully investigate the protective effects of systemic and local administration of RXRα-specific ligand K80003 on vulnerable atherosclerotic plaques. The overall purpose of this project is to provide new ideas and methods to stabilize the existing atherosclerotic plaques and to prevent acute cardiac events.