IRE1α-XBP1经磷脂代谢Kennedy通路调节新生儿脓毒血症宿主细胞内质网应激的研究

严重感染是新生儿死亡的重要原因，能量代谢紊乱是感染演进的重要特征，但调控具体机制不明。申请人前期研究发现败血症新生儿脂代谢标记物（酰基肉碱）水平与疾病转归有关，且组学分析显示磷脂合成经典通路Kennedy通路在感染时表达上调，其代谢产物主要参与内质网扩张，推测内质网应激关键协调因子XBP1经IRE1α激活后，参与了Kennedy通路调控，上调感染时宿主细胞的内质网应激，发挥细胞保护效应。本课题拟从队列、动物模型和细胞机制研究：①新生儿脓毒血症预警模型；②组织学水平，研究IRE1α-XBP1对感染时的宿主靶细胞磷脂合成的调节作用及细胞保护效应；③体外研究IRE1α-XBP1对Kennedy通路限速酶乙酰氨激酶和胆碱激酶的表达调控，探讨IRE1α-XBP1通过能量代谢通路对细胞的保护机制。最终阐明该脂代谢通路对新生儿脓毒血症靶器官的保护机制，为脂代谢干预策略提供科学依据。

Severe infection is an important cause of neonatal death, and energy metabolism disorders are important features of infection evolution. However, the specific mechanism of energy metabolism regulation is unknown. In our previous study, we found that the levels of lipid metabolism markers (acyl carnitine) in neonates with sepsis were related to the disease outcome, and analysis of differential metabolites in lipid metabolomics showed that the classical pathway for phospholipid synthesis, the -Kennedy pathway, was up-regulated at the time of infection. The metabolites of Kennedy pathway are mainly involved in endoplasmic reticulum expansion. Therefore, we speculated that XBP1, a key coordination factor for endoplasmic reticulum stress, was involved in the regulation of Kennedy pathway after it was activated by IRE1α, to up-regulate the endoplasmic reticulum stress in host cells during infection and exert cell protection. This study will include cohort, animal and cell studies. ① Establish an early warning model of neonatal sepsis. ②Investigate the regulatory effect of IRE1α-XBP1 on the synthesis of phospholipids of host target cells during infection and the cell protection effect. ③Investigate the regulation of IRE1α-XBP1 on the expression of the rate-limiting enzymes acetylcholine kinase and choline kinase in the Kennedy pathway, detect intracellular fat body content and endoplasmic reticulum stress level, and investigate the protective mechanism of IRE1α-XBP1 on cells through energy metabolism pathway. Finally, we would clarify the protective mechanism of lipid metabolism pathways on target organs of neonatal sepsis and provide a scientific basis for lipid metabolism intervention strategies.