Mechanisms of Trichothecene Toxicity

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DESCRIPTION (provided by applicant): The trichothecenes, a large group of fungal toxins that are commonly encountered as food contaminants, have been etiologically linked to human gastroenteritis worldwide and are of further concern for their potential use in chemical terrorism and warfare. Trichothecenes and other ribosome-directed agents (eg. ricin, shiga toxin) activate mitogen-activated protein kinases (MAPKs) and subsequently initiate inflammatory gene expression and apoptosis via a mechanism known as the "ribotoxic stress response", however, little is known of the specific signal transduction mechanisms involved. The objective of this proposal is to identify the intracellular signaling pathways and mechanisms by which the model trichothecene deoxynivalenol (DON or "vomitoxin") induces p38 MAPK activation and relate these to inflammation and apoptosis. Our central hypothesis is that double stranded RNA-activated protein kinase (PKR) and hematopoietic cell kinase (Hck) are critical for trichothecene-induced p38 activation and downstream toxicity. To test this hypothesis, our research team will use 1) knockout mice to verify roles for PKR and Hck in p38 activation and downstream toxicity and 2) macrophages to elucidate signal transduction elements that link DON to p38 via PKR and Hck. Four specific aims are proposed: 1) Characterize the role of PKR in DONinduced p38 activation and downstream toxic effects; 2) Characterize the role of Hck in DON-induced p38 activation and downstream toxic effects; 3) Assess role of the ribosome in DON-induced p38 activation; and 4) Evaluate role of Toll-like receptors in DON-induced p38 activation. This project will enhance public health by: 1)improving molecular understanding of how these trichothecenes and ribotoxic chemicals disrupt gut immunity, 2) enhancing our capacity to assess and manage risks associated with exposure to these agents and 3) generating mechanism-based strategies for preventing and/or treating toxicity in persons exposed to these compounds via natural contamination or chemical terrorism/warfare.