磷脂酰丝氨酸靶向超声造影剂对缺血性脑卒中小胶质细胞功能的调控及作用机制研究

脑缺血坏死激活脑内M2小胶质细胞向M1型转化，加剧神经元的死亡。针对继发炎症，抑制M1活性、促进M2转化以利于神经突触的再连接和重塑神经功能网络是脑卒中治疗的关键问题。我们前期研究表明，超声联合磷脂酰丝氨酸（PS）微泡可暂时性开放血脑屏障，同时高效靶向激活的小胶质细胞实现脑缺血后炎症区域有效的药物传输。本研究拟构建PS修饰的载短效糖皮质激素的微泡，靶向缺血区小胶质细胞，抑制M1炎症反应，同时促进M2的增殖及神经功能网络的形成，探究其对缺血性脑卒中小胶质细胞的调控及作用机制；同时追踪微泡运动轨迹进行脑超声微血管成像，基于神经血管单位是神经活动基本单元，探究该成像在监控小胶质细胞调控后神经功能网络形成过程中的应用价值。本项目通过研究靶向递送及成像监控的一体化PS超声造影剂对缺血性脑卒中小胶质细胞的调控及作用机制，以及微血管成像对神经功能形成的监控价值，为脑卒中炎症的诊断和治疗提供研究基础。

The reaction of cerebral ischemic necrosis transforms M2-type microglia to M1-type ones, which aggravates neural damage. In view of inflammation, inhibiting the M1-type microglia activity and promoting their transformation to M2-type phenotype, which can facilitate synaptic reconnection and reshape neural functional network, are the key issues in stroke treatment. In the preliminary study, the approach of the phosphatidylserine (PS)-modified microbubbles could temporarily open blood-brain barrier, achieving novel delivery routes for targeting the inflammation area by the activated microglia. Herein, the applicants proposed a novel and tactic strategy by using PS-modified microbubbles loading short-term glucocorticoids (GCs) to target microglia at the ischemic site. The M1-type microglia can be inhibited and transformed to M2-type ones, which will contribute to the reconstruction of neural functional network. We study of the mechanism for ischemia stroke by regulating microglia with targeted PS-modified microbubbles and achieve cerebral ultrasound microvascular imaging by tracking the movement of microbubbles. This imaging can be applied to monitor the activities of neural functional network by microglia regulation based on the theory of neurovascular unit (NVU). Therefore, the construction of PS-modified microbubbles with targeted delivery function and imaging monitoring integrates different effects, including studying of the mechanism by regulating microglia, and detecting neural functional network with ultrasound microvascular imaging, which can provide research basis for the diagnosis and treatment of stroke inflammation.