经颅聚焦超声联合微泡对血脑屏障调控及机制研究

Blood brain barrier is the barrier structure between peripheral circulation and central nervous system. Physiological blood brain barrier (BBB) protects the central nervous system from exotic harmful substances invasion, but when the central nervous system disease, blood brain barrier also prevented the drugs into the central nervous system. Low frequency focused ultrasound combined with micro bubbles has the characteristics of targeted, reversible, noninvasive open blood brain barrier, has become the most effective way to open blood brain barrier, its mechanism is still not clear.Our previous study have demonstrated the optimum parameters of open blood-brain barrier, which was obtained from focused ultrasound combined with micro-bubble in vivo animal model. In this study, we will originally establish the animal model of open blood-brain barrier in vivo， and try to establish the in vitro model at the same time, and then apply the gastrodine plus focused ultrasound with micro-bubble technology on the curative effect of alzheimer's disease transgenic mice. In the future, we will observe the effects of them, and then analyze the signal pathways related to the blood brain barrier open, as well as exploring the best parameters of ultrasound combined with micro bubble in vitro and in vivo. As a result, we will demonstrate the effects and mechanism of focused ultrasound plus micro-bubble on the opening of the blood-brain barrier; which will illustrate j reliable technical method and theoretical basis of treatments of clinical diseases of the central nervous system.

血脑屏障是外周循环与中枢神经系统之间的屏障结构。生理情况下血脑屏障保护了中枢神经系统不受外来有害物质侵入，但当中枢神经系统产生疾病时，血脑屏障也阻止了大部分治疗性药物进入中枢神经系统。低频聚焦超声联合微泡具有靶向性、可逆性、无创性开放血脑屏障的特点，成了目前开放血脑屏障有效的方法，其机制仍不清楚。我们前期研究已获得体内聚焦超声联合微泡开放血脑屏障的动物模型最佳超声参数，本次研究我们除了建立体内血脑屏障模型外，同时还尝试建立体外模型，并以天麻素为药物介导，运用聚焦超声联合微泡技术观察天麻素对阿尔茨海默病转基因小鼠的疗效，并从体内外两个方面研究与血脑屏障开放的相关通道蛋白以及探寻体外超声联合微泡的最佳参数，进而阐明聚焦超声联合微泡对体内外血脑屏障模型的影响并探讨血脑屏障开放的机制。为临床中枢神经系统疾病治疗提供可靠的技术手段及理论依据。

血脑屏障(The blood-brain barrier ,BBB)是外周循环与中枢神经系统之间的屏障结构。生理情况下血脑屏障保护了中枢神经系统不受外来有害物质侵入，但当中枢神经系统产生疾病时，血脑屏障也阻止了大部分治疗性药物进入中枢神经系统。阿尔兹海默病是目前最为常见的神经退行性疾病之一，其发病率高，目前尚缺乏有效的治疗方法，为世界医疗带来了巨大挑战。本项目围绕经颅聚焦超声联合微泡对血脑屏障调控及机制研究在体内和体外实验中做了大量研究工作。体外研究中课题组成功建立了BBB细胞模型并探索出FUS-MB开放BBB的最佳体外参数，并且成功建立了体外FUS-MB开放BBB的药物递送系统，可增加不同分子量药物的BBB透过率。此外，课题组研制的脂质PLGA杂合微泡可包裹荧光探针和天麻素，在检测凋亡事件的同时发挥抗凋亡作用，为聚焦超声联合微泡开放血脑屏障诊疗一体化提供了新视角，并且促进该技术向临床转化；体内部分课题组经过大量努力探索出聚焦超声和平面超声安全开放小鼠BBB的最佳参数并证明了其可逆性，同时明确了FUS-MB联合天麻素治疗AD小鼠的疗效，Y迷宫行为学结果显示FUS-MB联合天麻素可逆转Aβ1-42侧脑室注射导致的记忆功能障碍，使之接近正常小鼠记忆水平。本项目研究成果为AD治疗药物的开发以及治疗方式的多样化提供研究基础，促进FUS-MB治疗疾病向临床转化，具有重要的社会意义和经济价值。