Cell signaling in exercise and sterile inflammation.
We study cell signaling pathways activated by exercise and sterile inflammation. Extracellular histones are elevated after trauma and have been linked to endotheliopathy. Using intact vascular preparations from mice and human subjects, we found that histones
induce large endothelial calcium transients which are paradoxically uncoupled from vasodilation and instead lead to cell death. The results of these studies provide mechanistic insight into the fundamental mechanisms of endothelial injury in sterile
inflammation. This NIH-funded research has provided a critical and necessary basis for the development of novel therapeutic strategies that can protect the endothelium, decrease edema and multi-organ failure, and improve survival after trauma.
For example, we identified a small molecule therapeutic which is the subject of a US Patent application (July 2018, UVM Ref. No. C717). Our patent involves a novel mechanism to effectively bind and neutralize cytotoxic circulating histones for treatment
of severe acute inflammatory states including trauma.
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