Research Project 2

研究项目2将弥合对珊瑚礁产毒冈比亚圆盘鱼生态的了解 (在研究项目1中确定)和人类暴露和毒性(在研究项目3中评估)。 具体地说，项目2将评估产毒冈比亚圆盘藻产生的代谢物及其通量和 向海洋食物网转移的机制以评估生物积累的速度， 运输和生物转化，以及净化。我们将包括毒素和毒素的生态生理学研究 硫磺渗透剂，二甲基磺基丙酸酯(DMSP)生产冈比亚。我们假设DMSP， 在冈比亚的胞内浓度为100 mM时产生的，可能具有保护作用 (可能通过抗氧化活性)对抗毒素对生产者和消费者的影响 代谢物在食物链中移动。这些调查的结果将对发展至关重要 在毒素通量模型和人类健康风险评估中的应用。项目2还将侧重于确定 在急性和亚致死暴露后，在模式鱼类中上调的过程/机制，以 确定可能有助于深入了解雪卡毒素毒理效应的代谢物和生物标志物。 因此，拟议的研究将侧重于使用暴露于环磷酰胺的多种模型系统， 并使用集成的“组学”方法，以确定并随后验证CTX暴露的生物标记物，作为 很可能是生物蓄积的代表。有了这些结果，我们将继续开发原位毒素的方法 检测和潜在的诊断或预后方法。这些研究将与有针对性的 研究评估细胞环磷酰胺转运机制，解毒机制，DNA损伤，和 氧化应激(与DMSP的产生和转化有关)。项目2的新的综合方法， 将带来先进的分析方法来解决一个长期存在的问题，即试图提供生物标志物 以及最终将限制人类接触CTX的预测工具。

Research Project 2 will bridge the gap between knowledge of the ecology of toxigenic Gambierdiscus on the reef (established in research project 1) and human exposure and toxicity (evaluated in research project 3). Specifically, Project 2 will evaluate the metabolites produced by the toxigenic Gambierdiscus and their flux and mechanisms of transfer into the marine food web to assess the rates of bioaccumulation, mechanisms of transport and biotransformation, and depuration. We will include ecophysiology studies of both toxin and the sulfur osmolyte, dimethylsulfoniopropionate (DMSP) production Gambierdiscus. We hypothesize that DMSP, which is produced at >100 mM intracellular concentrations in Gambierdiscus, may have protective effects (possibly via antioxidant activity) against the effects of the toxin in the producers and consumers as both metabolites move through the food web. The results from these investigations will be critical for the development of toxin flux models and in the assessment of human health risk. Project 2 will also be focused on determining processes/mechanisms that are upregulated in model fish species following acute and sub-lethal exposure, to identify metabolites and biomarkers that may provide insight into the toxicological effects of ciguatoxin. Accordingly, the proposed research will focus on the use of multiple model systems of finfish, exposed to CTX, and use an integrated “omics” approach, to identify and subsequently validate biomarkers of CTX exposure, as a proxy of likely bioaccumulation. With these results we will move toward development of methods for in situ toxin detection and potential diagnostic or prognostic methodologies. These studies will be coupled with targeted investigations to evaluate cellular CTX transport mechanisms, detoxification mechanisms, DNA damage, and oxidative stress (linked with DMSP production and transformation). The novel integrated approach of project 2, will bring advanced analytical methodologies to bear on a long-standing problem of trying to provide biomarkers and forecasting tools that will ultimately limit exposure of humans to CTX.