PSTK基因异常表达在百草枯中毒致肺损伤中的作用及机制研究

Paraquat (PQ) is a type of widely used hericides, and is often used as a common poision in both accidence and sucide.The main cause of PQ induced death is oxidative stress-induced lung injury. Previously we assayed gene spectrum of lung tissue of PQ induced lung injury, and classified 35 core genes related to PQ. Among these PSTK is the only gene that is related to selenium proteins, and we also observed that PSTK gene knockout C-elegans exhibited shorter survival rate than the wide type when both were challenged by PQ. For the sake of anti-oxidiant properties of selenium proteins, and also it is Sec that works as a turn on/off point during anti-oxidiant function of selenium, furthermore,Sec is regulated by PSTK gene, we propose at first time that the aberrant of PSTK gene expression is the reason contributing to inability of anti-oxidiant effect of Selenium, leading to the pathegenosis of PQ induced lung injury. To vertify this hypothesis, firstly we will determine how PSTK gene knockout affects the PSTK kinase, Sec synthesis and oxdiative stress related selenium proteins; these results will further be confirmed by the data from PQ patient biopsy. Lastly we will supply PQ mice with external selenium to observe surivival status and lung injury. It is predictable that the data of this project will not only help us deepen understanding of mechanism of of PQ lung injury, but also provide PQ patients with promising treatment of using both PSTK intervention and selenium.

百草枯(PQ)自杀和意外中毒在我国发生率高，中毒死亡率高，其直接死因为氧化应激引起急性肺损伤。前期我们检测了PQ中毒肺组织基因表达谱，确定了35个关键调控基因，其中PSTK是惟一调控硒蛋白的基因；PSTK基因敲除PQ中毒线虫生存时间显著缩短，PQ中毒患者血液PSTK蛋白水平显著降低。由于硒代半胱氨酸（Sec）是硒酶和硒蛋白抗氧化的活性中心，而Sec受PSTK基因调控。故我们推断PSTK异常表达导致硒蛋白抗氧化活性下降是PQ中毒致肺损伤的重要病理机制。为证实该推断，我们首先研究PQ中毒对PSTK基因敲除线虫PSTK激酶和Sec合成的影响；之后确定PQ中毒对PSTK基因调控的相关硒蛋白的改变及其与肺损伤的关系；最后观察补硒对PQ中毒小鼠生存时间和肺损伤的影响。本课题结果不仅深化了对PQ中毒肺损伤机理的认识，还为研究基于干预PSTK基因和采用硒蛋白联合治疗PQ中毒新方案提供实验证据。

1.我们研究了PSTK基因在氧化应激模型中小鼠肺组织表达与肺病理改变的关系。发现PSTK是百草枯中毒肺损伤的核心基因之一；.2. 发现PSTK在肾脏足细胞中高表达能够部分抑制顺铂引起的细胞氧化应激损伤相关基因表达；.3. 发现系列硒蛋白保护药物足细胞损伤部分机制，包括BCL-2/BAX/caspase-3通路。