蛋白纳米颗粒渗透压调控脑缺血星形胶质细胞水肿机制及其相关治疗药物研究

星形胶质细胞（As）水肿是脑缺血等众多疾病治疗面临的医学难题。依据渗透压是调控水进出细胞的驱动力，申请人实验室创建了角度中间纤维张力探针，将渗透压牵拉的骨架张力变化转换为实时光学信号，发现：缺血能刺激As微丝微管解聚，生成大量蛋白纳米颗粒，通过吸附阳离子，诱导As渗透势能上调及脑水肿发生，符合“唐南效应”。然而，“唐南效应”并未合理解释纳米颗粒吸附离子能力改变及游离阳离子减少对膜两侧电位的影响。本研究将引用纳米“双电层压缩”理论，解析脑缺血蛋白颗粒生成先诱导As低渗和超极化，激活HCN等电压门控离子通道，调控钠离子内流及电位恢复；但是后续T和L型钙通道导入的二价离子，反而促进蛋白颗粒释放一价阳离子，诱导阴离子内流、胞内高渗和水肿发生；同时揭示脑缺血胞内骨架解聚诱导蛋白颗粒生成的化学信号机制。藉此以降低胞内渗透势能为靶标，筛查治疗缺血性脑水肿的药物组合，探寻脑病治疗的新药研发方向。

Astrocyte edema is a medical problem in the treatment of many diseases such as cerebral ischemia. According to the preliminary research that osmotic pressure serves as the driving force regulating water flow across living cells, our laboratory created angle tension probes and integrated them into the intermediate filament, which converted the osmotic pressure variation in living cells into the optical signals. Our study found that ischemia stimuli resulted in the depolymerization of intracellular microfilament and microtubules, producing a mass of protein nanoparticles in astrocytes. The intracellular nanoparticles induced the up-regulation of permeability potential through the adsorption of cations, and then contributed to occurrence of cerebral edema. Although the above phenomenon is consistent with the "Donnan Effect" theory, it is insufficient to reasonably explain the variable ability of nanoparticles to adsorb ions and the effect of decreasing free cation on the membrane potential. In this present study, according to "the double-layer compression" theory, we will analyze that the generation of protein nanoparticles can induce hyperpolarization of astrocytes in response to ischemia, subsequently activate the various voltage-gated ion channels and upregulate intracellular ions, especially the T and L-type calcium channel. Influx of divalent ions enables to induce the release of monovalent ions from protein nanoparticles, resulting in up-regulation of osmotic pressure and occurrence of astrocyte edema. In addition, we will reveal that the molecular mechanisms underlying depolymerization of intracellular microfilament and microtubules and production of mass protein nanoparticles in cerebral ischemia. The study aims to reveal the pathogenesis of astrocyte swelling and brain edema in ischemia stimuli, develop new drugs in the area of osmotic potential, and explore the new pharmacological mechanisms and drug development direction for the treatment of brain edema.