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Apical membrane endosomal trafficking in digestive epithelia is the primary mechanism by which foodborne toxins gain entry across the mucosal barrier. One of the primary signaling mechanisms governing endosomal trafficking is the acute elevation of intracellular Ca2+, which occurs in response to neural and humoral stimulation of cells. We have identified that the Ca2+/calmodulin regulated protein kinase II (CaMKII) is highly localized to an early endosomal compartment in digestive epithelial cells.<P> The primary objective of this proposal is to test the hypothesis that CaMKII is an important regulatory enzyme modulating the endocytosis, sorting and trafficking of cholera and shiga toxins in digestive epithelia.
Non-Technical Summary: The cellular process termed endocytosis mediates the uptake and delivery of a number of toxins that are released by micro-organisms to cause foodborne illness. The most well characterized toxins affecting the intestinal tract include the deadly plant toxin ricin, and the bacterially derived cholera and shiga toxins that are transmitted in contaminated food and water. The epithelial cells lining the intestine create a barrier and thereby provide the first line of defense against foodborne pathogens. This project is aimed at understanding the mechanism by which toxins infiltrate the digestive system. <P> Approach: In Specific Aim 1 CaMKII specific inhibitors will be used to define a functional role for the enzyme in toxin-associated endosomal trafficking. Specific Aim 2 will directly investigate the role of CaMKII on early endosomal fusion reactions using an in vitro system. It is anticipated that the results obtained will provide valuable insight into the mechanism by which foodborne toxins invade digestive epithelia cells to cause disease.