原卟啉IX敏化超声辐射力致机械敏感性离子通道Piezo1的开放促进巨噬细胞吞噬功能逆转动脉粥样硬化斑块

Although vascular reconstruction could save lives and raise living quality of atherosclerosis (AS) patients, it has a high perioperative mortality and restenosis rate. The exploration of treatment and research targeting macrophage (Mφ), a pivotal element throughout the progression of AS, could offer a fundamental solution for AS. This project would verify that protoporphyrin IX (PpIX) could preferentially accumulate on the membrane of Mφ and decrease the threshold of ultrasound-induced Piezo1（a new type of mechanosensitive ion channel）opening, which increases the concentration of intracellular Ca2+ and promotes Mφ phagocytosis and AS regression. We would clarify the mechanism of PpIX- facilitated Piezo1 opening by ultrasonic radiation force, and uncover the pivotal role Mφ phagocytosis during AS progression. This study would explore a new treatment strategy targeting the pathogenesis of AS and lay the foundation for the development of a noninvasive, safe and accurate target therapy for AS.

血管重建术虽然挽救了动脉粥样硬化（AS）患者的生命并改善了其生活质量，但围手术期死亡率及再狭窄发生率均较高。针对AS进展中发挥核心作用的巨噬细胞（Mφ）进行治疗和研究的探索，能从根本上解决AS进展的问题。本课题拟通过体外Mφ细胞模型，体内利用apoE基因敲除小鼠及兔股动脉球囊损伤AS模型来验证原卟啉IX（PpIX）可选择性聚集并结合于Mφ的细胞膜上，通过改变膜张力降低超声辐射力致新型机械敏感性离子通道Piezo1开放的阈值，通过联合低强度超声靶向增加Mφ内Ca2+的浓度，进而促进Mφ的吞噬功能逆转AS斑块，同时减小对周围正常组织的损伤。课题将阐明PpIX与低强度超声联合开放Piezo1通道进而促进Mφ吞噬功能的机制，揭示Mφ的吞噬功能在AS进展中的核心作用。为临床针对AS病变的发病机理进行治疗开拓新的方法，为发展无创、安全、精准靶向治疗AS的技术奠定可靠的实验基础。

血管重建术虽然挽救了动脉粥样硬化（AS）患者的生命并改善了其生活质量，但围手术期死亡率及再狭窄发生率均较高。针对AS进展中发挥核心作用的巨噬细胞（Mφ）进行治疗和研究的探索，能从根本上解决AS进展的问题。本课题通过体外Mφ细胞模型，体内利用apoE基因敲除小鼠及兔股动脉球囊损伤AS模型来验证原卟啉IX（PpIX）可选择性聚集并结合于Mφ的细胞膜上，通过改变膜张力降低声辐射力致新型机械敏感性离子通道Piezo1开放的阈值，通过联合低强度超声靶向增加Mφ内Ca2+的浓度，进而促进Mφ的吞噬功能逆转AS斑块，同时减小对周围正常组织的损伤。课题阐明l了PpIX与低强度超声联合开放Piezo1通道进而促进Mφ吞噬功能的机制，揭示了Mφ的吞噬功能在AS进展中的核心作用。为临床针对AS病变的发病机理进行治疗开拓了新的方法，为发展无创、安全、精准靶向治疗AS的技术奠定了可靠的实验基础。