SEC14L3激活PI3K/Akt信号通路调控BaP与DEHP致细胞损伤的机制研究

人类长期、低剂量暴露室内环境多种污染物可危及其健康，研究室内环境重要污染物的毒理机制是环境卫生研究的重要内容之一。苯并芘(B[a]P)和邻苯二甲酸二乙基己酯(DEHP)是现代居室环境中重要的污染物。研究发现PI3K/AKt通路参与这两种污染物诱导的细胞氧化应激和炎症反应，细胞损伤甚至死亡的生物学效应的调控。Sec14L3是近年备受关注的新气道标志物，它参与胆固醇生物合成过程，而磷脂酰肌醇-3,4,5-三磷酸(PIP3)是SEC14L3的特定配体。不过，SEC14L3在这两种环境污染物诱导的氧化应激和活化PI3k/Akt通路中的调控机制仍不十分清楚。本项目拟用人肺细胞和人肝细胞建立B[a]P和DEHP联合染毒细胞模型，初步明确B[a]P和DEHP经氧化应激与炎症反应介导的线粒体功能障碍和细胞损伤的联合毒性作用，重点研究B[a]P和DEHP致细胞联合毒性作用中SEC14L3激活PI3K/Akt通路调控线粒体功能的机制，为SEC14L3作为机体炎症损伤预警指标提供科学依据。

Indoor air pollution is gradually gaining more attention as an important public health issue. The characteristics of health impacts of indoor air pollution are chronic low dose exposures and combined effects of multiple pollutants. Benzo[a]pyrene (B[a]P) and di(2-ethylhexyl)phthalate(DEHP) can induce oxidative stress and inflammatory response, as well as mitochodrial dysfucntion, cell injury and even cell death.PI3K/Akt signaling pathway regulates inflammentory response.The expression of Sec14L3 mRNA/protein is associated with the development of airway inflammation and regualtion of cholesterol biosynthetic process.PIP3 is a specific lagand for the SEC14L3 protein.However,SEC14L3 roles in the molecular mechanisms of oxidative stress and the activation of PI3K/Akt pathway are unclear.In the present study, the cell models of B[a]P and DEHP co-exposure will be created using several cell lines including A549(human lung epithelial cell line), normal human liver cell line), HepG2(Human hepatocellular liver carcinoma cell line). Subsequently, the indicators of oxidative stress, mitochondrial dysfunction and cellular injury were analyzed in the cell culture models. To provide scientific basis for SEC14L3 as a predictor of the inflammatory status, a potential linkage between SEC14L3 and the activation of PI3K/Akt signaling pathway in relation to the mitochondrial dysfunction was further investigated using the cell models.