基于超声多模态评价技术探讨肝脏靶向递送ABCA1新策略在动脉粥样硬化防治中的应用

截至目前，动脉粥样硬化（AS）的防治依然缺乏有效手段。既往发现肝脏合成的高密度脂蛋白（HDL）对胆固醇逆向运输及AS防治至关重要；而转运蛋白ABCA1是HDL加工成熟的关键分子，AS时多伴有ABCA1功能降低。因此，增强肝脏ABCA1功能，有望提升HDL合成能力，从源头上防治AS。可见，肝脏递送ABCA1这一膜分子是解决该问题的关键。课题组发现，外泌体具有良好的肝脏靶向性，是肝脏递送ABCA1的理想载体。本项目拟在此基础上，利用光遗传和基因工程技术等改构外泌体，使其外表面携带ABCA1，内部加载能够增强内源ABCA1表达的小核酸，实现双途径增强肝脏ABCA1的表达；然后结合超声评价AS的优势，利用AS小鼠模型探讨外泌体递送ABCA1防治AS的效果；最后，通过临床样本分析AS患者ABCA1表达异常的分子机制，为新策略的优势提供临床依据。本项目在加深AS机制认识的同时，有望为其防治提供新思路。

Atherosclerosis (AS) is a prevalent and life-threaten disease. Currently, there are still no effective therapeutic strategies. Developing the prevention and therapeutic strategies is essentially important for both the patients and the society. Recent studies have revealed that the HDL (high density lipoprotein) synthesized by the liver plays an important role in the reverse cholesterol transport and thus AS development. Moreover, the ATP-binding cassette transporter ABCA1 has been found to be essential for the HDL synthesis and maturation, while aberrant low expression of ABCA1 in the liver has been linked to AS. In view of these data, we assumed that targeted increasing the expression of ABCA1 in the liver would be a promising to enhance the HDL level and thus be beneficial for AS prevention and therapy. With the funding support of NSFC, we found that exosomes preferentially circulate into the liver. In addition, we have developed an exosome based strategy for specific enhancing gene expression in targeted cells or tissues. Briefly, we have engineered the exosomes to carry the target protein on the surface and encapsulate the inhibitors for the inhibitory endogenous miRNAs inside. The engineered exosomes thus are more potent in enhancing target protein expression in the recipient cells. In the proposed project, we would develop a liver specific ABCA1 delivery strategy based on the previous experience on exosome engineering. Next, we would systemically analyze the efficacy and side effects of the new ABCA1 delivery strategy on the AS prevention and therapy in the mouse model by ultrasound based evaluation. Moreover, we would also analyze the possible molecular mechanisms responsible for the deregulated ABCA1 in AS patients, which would provide clues for the selection of the candidates for the strategy. Taken together, the current proposal would be promising in decoding the mechanism of atherosclerosis and establishing new treatments for the disease.