百草枯（Paraquat, PQ）是触杀型除草剂，PQ中毒危害大、死亡率高，心肺是PQ中毒损害重要的靶器官，然而PQ中毒具体机理及死亡机制仍不清楚，同时PQ中毒标志物的检测是PQ中毒的法医学评价及事故责任认定的基础，因此针对PQ中毒机理及生物标志物筛选开展研究工作具有重要意义。前期研究发现了氧化应激、钙离子信号通路、线粒体损伤、细胞周期和细胞死亡和炎症因子参与PQ引起的心肺损害，其具体机制仍需进一步阐明。本研究将从以下几个方面开展：1）明确Cav-1/Nox1/STIM1在PQ中毒中的重要作用，2）研究相关信号分子间的调控机制，3）PQ影响细胞周期和细胞死亡的分子细胞机制，4）寻找PQ中毒生物标志物。项目的实施将为阐明PQ中毒机理、中毒死亡原因和死亡机制提供可靠的理论基础，为法医毒理学研究提供新思路；针对PQ中毒后分子标志物进行筛查，为PQ中毒相关检测和毒物分析提供实践应用依据。

Paraquat (PQ, 1, 1’-dimethyl-4, 4’-bipyridinium) is a highly toxic herbicide, which is widely used in numerous developing countries around the world. Ingestion of PQ leads to multiple organ damage especially in the heart and lung. PQ induced cardiac dysfunction and progressive pulmonary fibrosis, which is often associated with high mortality, appears as early as several hours to several weeks after PQ ingestion. However, the underlying molecular mechanisms of which remain elusive. Meanwhile, the identification of the biomarker for paraquat toxicity is important for the area of forensic toxicology and identifying a crime. Therefore, it is important to study the mechanisms and identify the biomarkers in paraquat induced organ injury. In our preliminary data, we have found that the overproduction of reactive oxygen species, calcium signaling, mitochondrial dysfunction, the blockage of cell cycle and cell death are involved in paraquat induced cardiac and pulmonary injury, however the detailed mechanisms remain to be defined. This application will address the deficits in our knowledge by: 1) establishing a functional significance of Cav-1/Nox1/STIM1 signaling pathway in paraquat induced cardiac and pulmonary injury, 2) identifying the molecular regulatory mechanism of signaling molecules in paraquat toxicity, 3) understanding the impact of cell cycle and cell death by paraquat in the heart and lung, 4) identifying the diagnostic biomarkers for paraquat toxicity. Our study will provide a better understanding on the cellular and molecular mechanism underlying paraquat induced cardiac and pulmonary injury as well as the death caused by paraquat. We anticipate the development of novel therapeutic agents targeting Cav-1/Nox1/STIM1 signaling pathway that will help reduce paraquat induced organ injury and subsequently reduce the morbidity and mortality. We will also identify the potential biomarker and development the diagnostic approaches which will be beneficial for forensic practice.