肥大细胞激活在小鼠脓毒症相关性脑病中的作用及机制研究

脓毒症诱导的中枢炎症过度激活是促使脓毒症相关性脑病（SAE）发生发展的重要因素。然而，作为机体固有免疫系统的一种多功能效应细胞，肥大细胞在SAE中扮演的角色却鲜有报道。鉴于肥大细胞能在中枢炎症反应中迅速激活，并释放多种炎性介质介导中枢炎症级联放大反应的生物学特性，我们推测肥大细胞在SAE病理状态下存在过度激活，并且对SAE的发生发展有重要作用。本项目中，我们将首先明确SAE病变下肥大细胞的激活状态，并利用野生型小鼠及肥大细胞缺陷型小鼠协同证实肥大细胞在SAE中的重要作用；其次，分别在体内实验及体外实验中深入分析肥大细胞激活对血脑屏障及脑微血管内皮细胞功能的影响，以及组胺-LPS-TLR4-ASK1信号通路在其中的重要作用，揭示肥大细胞介导SAE的病理及分子机制；此外，我们还将进一步在小鼠模型中探讨肥大细胞干预药物对SAE的治疗意义。上述研究将可能对SAE的发病机制及临床治疗提供新的思路。

Sepsis induced neuroinflammation has been demonstrated as a key factor in the pathogenesis of sepsis associated encephalopathy (SAE). Mast cells (MCs) are integral part of the innate immune system. The significant elevations of MCs number and degranulation within minutes in association with stimulus enables MCs action as catalysts that amplify and prolong numerous neuroinflammation responses. However, the role of MCs in SAE has still not been well studied. Given the first-responder capability of MCs, we hypothesize that MCs are abnormal activated under SAE situation, and play a critical role to the pathology of SAE. To pursue this hypothesis, our project proposes the following specific studies: firstly, we will establish mouse SAE model and detect the number and activation of MCs. The important role of MCs in SAE will be further confirmed by using wild type mice and MCs-deficient mice. Secondly, we will determine the effect of MCs on blood brain barrier and brain microvascular endothelial cells, and the importance of Histamine-LPS-TLR4-ASK1 signaling, by using series of in vivo and in vitro tests, to uncover the mechanisms how MCs mediate the SAE pathological process. Furthermore, in mouse model, we will also explore whether pharmacological intervention of MCs responses could ameliorate the SAE progression. The results of this project will support an important role for MCs activation in SAE and suggest that inhibition of this response could be a new target for SAE clinic treatment.