NLRP3炎症小体通过p97介导AMPA受体内吞在新生鼠缺氧缺血性脑损伤中的作用及其机制研究

HIE是围产期最常见的中枢神经系统疾病，主要表现为运动和认知功能障碍，目前尚缺乏有效的防治措施。研究报道NLRP3炎症体在缺氧缺血引起的成年脑损伤中发挥重要作用。然而，NLRP3炎症体是否以及如何参与未成熟大脑HIE的发生发展并不清楚。我们预实验发现，HIBD模型鼠脑组织中NLRP3炎症体相关蛋白呈时间依耐性表达上调，而突触后膜上AMPA受体亚基GluA1的表达显著降低。结合最新研究报道，p97可与突触后GluA1相互作用调控其转运。我们推测：缺氧缺血激活NLRP3炎症体，活化的caspase-1促进下游IL-1β成熟和分泌，进而触发p97介导AMPA受体内吞，导致运动和认知功能障碍。为了验证这一假设，本项目拟结合行为学、药理学和基因干预等技术，从基因、分子、细胞和整体的不同层面阐述NLRP3炎症体通过p97介导AMPA受体内吞在HIBD中的作用及机制，为临床防治HIE提供新的思路和靶点。

Hypoxic-ischemic encephalopathy (HIE) is the most common perinatal diseases of the central nervous system, which is characterized by motor and cognitive impairments. However，there is no effective way to cure HIE-related diseases so far. Recent studies have found that NLRP3 inflammasome plays an important role in adult brain damage induced by hypoxia-ischemia. However, it is unclear whether and how NLRP3 inflammasome is involved in the development of HIE in newborns. Our preliminary experiments showed that the expressions of NLRP3, cleaved caspase-1 and IL-1β were significantly increased in a time dependent manner in hypoxic-ischemic brain damage (HIBD) model rats. We also found that synaptic GluA1 amount was markedly decreased following HIBD. Combining recent report that p97, a type II AAA ATPase, plays an important role in regulating GluA1 trafficking, we hypothesize that HIBD leads to activation of inflammasome, increases downstream IL-1β activity, and then triggers p97-mediated GluA1-containing AMPA receptor endocytosis, which ultimately leads to synaptic plasticity impairment and motor and cognitive dysfunction. In order to investigate this hypothesis, we intend to use a combination of behavioral, pharmacological and genetic intervention assessments. Knowledges gained from the present study may thus provide novel approaches and new target for the prevention and treatment of HIE in clinical settings by deepening our understanding of the molecular mechanism underlying HIBD at gene, molecular, cellular and whole-organism levels.