TRPM2调控小胶质细胞LAPosomes成熟参与脓毒症脑病的机制研究

A study has indicated that sepsis-associated encephalopathy (SAE) occurred in 70% of septic patients. SAE is associated with increased mortality and the morbidity of long-term cognitive impairments. Transient Receptor Potential Melastatin 2 (TRPM2), a nonselective Ca2+-permeable channel, is expressed abundantly in immunocytes such as macrophage and microglia. Our previous study had demonstrated that TRPM2 induced Ca2+ influx plays a critical role in host defense against invading bacteria via promoting phagosome maturation. Several studies had confirmed that inflammatory response of microglial phagocytosis is an important mechanism of SAE. However, the role of microglial TRPM2 in phagosome degradation during SAE and its underlying mechanism remain unclear. Using microglia from Trpm2 or Vps34 knockout mice, we will explore detailed molecular mechanism of TRPM2 induced Ca2+ influx on the effect of NOX2 activity and LAPosomes-lysosomes fusion. Meanwhile, the role of TRPM2 in the development and progression of SAE also need to be clarified. Our study will provide novel intervention targets and theoretical basis for clinical prevention of SAE.

脓毒症脑病（SAE）发生率高达70%，SAE患者死亡率居高不下，存活者长期预后堪忧。瞬时受体电位通道M2（TRPM2）是高表达于免疫细胞上的氧化应激敏感的非选择性Ca2+通道。申请人的前期研究重点探讨了巨噬细胞TRPM2在病原体入侵即时通过介导Ca2+内流参与吞噬体成熟和细菌降解的过程[14]。研究证实小胶质细胞吞噬性炎症反应是SAE的重要病理基础。TRPM2通道是否调控小胶质细胞LAPosomes成熟并参与SAE的发生发展过程，亟待研究证实。本研究利用TRPM2-/-和Vps34-/-小鼠，以小胶质细胞为切入点，探讨TRPM2介导Ca2+信号内流抑制吞噬体上NOX2活性和LAPosomes成熟的分子机制，并阐明其在SAE发生发展中的作用，为SAE治疗提供新靶点和理论依据。

脓毒症脑病（SAE）发生率高达70%，SAE患者死亡率居高不下，存活者长期预后堪忧。瞬时受体电位通道M2（TRPM2）是高表达于免疫细胞上的氧化应激敏感的非选择性Ca2+通道。我们最近发现TRPM2在吞噬体上高表达，进一步研究证明TRPM2介导的Ca2+内流在小胶质细胞LAP过程中的关键作用。深入的研究还表明TRPM2 介导 Ca2+内流抑制NOX2活性，阻断小胶质细胞LAPosomes成熟以及LAPosomes-溶酶体融合过程。这些研究为脓毒症脑病的发病机制提供了新的认识，并为进一步阐明TRPM2在SAE发生中的作用提供了新的可能。