Novel therapeutic targets for fluoroacetate-induced toxicities.

点击翻译按钮获取中文摘要

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.