全氟化合物毒性作用新靶点蛋白质酪氨酸磷酸酶的识别及分子机制研究

流行病学调查表明人类血液中全氟化合物（PFCs）浓度与一些癌症及疾病的发生呈显著正相关。蛋白质酪氨酸磷酸酶（PTP）是细胞信号传导过程的重要调节因子，参与多种细胞功能的调控，PTP活性失调会导致多种疾病甚至癌症的发生等。PFCs进入生物体后，是否会与疾病相关通路PTP相互作用并对PTP介导的通路产生干扰效应，仍属未知。本项目拟在前期酪氨酸磷酸化电化学传感器工作的基础上，研究PTP催化多肽磷酸化酪氨酸残基的去磷酸化反应，实现对PTP活性的免标记检测。利用建立的传感方法，快速筛查PFCs对PTP活性的干扰效应，并在细胞水平研究PFCs对筛选出的PTP活性的影响、对PTP介导的疾病相关通路的干扰和后续生物学效应、以及PFCs与PTP复合物形成与否，建立定量结构-活性关系模型。探讨PFCs毒性的新靶点及分子机理，该项目将为其它持久性有毒污染物毒性作用新靶点的体外筛查和分子毒理学研究提供一种新手段。

Epidemiological studies revealed a positive relationship between perfluorinated compounds (PFCs) concentrations in human blood samples and some diseases, even cancers. Protein tyrosine phosphatase (PTP) plays a central role in cellular signal transduction and involves in the regulation of a variety of cell functions. The dysregulation of PTP activity can induce the occurrence of some diseases, even cancers. When pollutant enters the organism, whether it can selectively interact with PTP involved in the disease-related signaling pathway, as well as the subsequent effect on the pathway is unknown. On the basis of our previous work about the biosensor of kinase-catalyzed tyrosine phosphorylation, a simple, fast and label-free electrochemical biosensor for the assay of PTP activity will be developed. Using the sensing method, the disturbing effect of PFCs on PTP activity will be screened. Moreover, the effect of PFCs on PTP activity, the disturbing effect of PFCs on PTP-mediated disease pathway and the subsequent biological effect, as wel as the assay of the PFC/PTP complex will be investigated at cellular level. The quantitative structure-activity relationship of PFCs will be established. The novel cellular target of PFCs and pathogenic mechanism will be explored in detail. Our study will provide a novel way for screening the cellular target of other pollutants and studying their molecular toxicology.