Novel therapeutic targets for fluoroacetate-induced toxicities.

暴露于氟乙酸酯(FA)会导致心脏、呼吸、神经和代谢的一系列变化 功能障碍可能是致命的。对FA中毒的解药几乎是不存在的，唯一可用的选择是 口服乙醇，只有在接触后立即给予才有效。此外 对于已知的FA中毒机制，我们的初步发现表明，糖酵解途径也是 被禁止了。我们的初步研究结果还表明，FA对心肌细胞和肺组织的毒性作用 增加糖酵解可以挽救上皮细胞。我们的假设是FA中毒可以通过 通过增加糖酵解通量来增加替代能量的产生。这将通过以下方式进行测试 特定目标：特定目标1将评估FA中毒后细胞、培养上清液、组织和血液中的代谢物水平以及糖酵解诱导剂的存在。特定目标2将测试增加糖酵解是否可以保护和 针对FA中毒的救援。这些研究将使用体外和体内两种方法进行。这个 体外研究将使用原代心肌细胞、神经元和肺上皮细胞。入内 活体研究将使用FA中毒的大鼠模型。拟议的研究结果将有助于确定治疗方法 FA中毒的选择以及与代谢中毒相关的其他潜在有毒化学品。

Exposure to fluoroacetate (FA) causes a spectrum of cardiac, respiratory, neurological, and metabolic dysfunctions that can be fatal. Antidotes to FA poisoning are virtually non-existent, the sole available option being the oral administration of ethanol, which is effective only when given immediately following exposure. In addition to known mechanisms of FA poisoning, our preliminary findings indicate that the glycolytic pathway is also inhibited. Our preliminary findings also demonstrate that FA poisoning of cardiomyocytes and pulmonary epithelial cells can be rescued by increasing glycolysis. Our hypothesis is that FA poisoning can be rescued by increasing alternate energy production through increased glycolytic flux. This will be tested through the following specific aims: Specific Aim 1 will assess metabolite levels in cells, media supernatants, tissues and blood after FA poisoning and in presence of the glycolysis inducers. Specific Aim 2 will test whether increasing glycolysis can protect and rescue against FA poisoning. These studies will be carried out using both in vitro and in vivo approaches. The in vitro studies will be carried out using primary cardiomyocytes, neuronal and pulmonary epithelial cells. The in vivo studies will use a rat model of FA poisoning. Results of the proposed research will help identify treatment options for FA poisoning as well as other potentially toxic chemicals associated with metabolic poisoning.