The long term objective of this study has been to determine what role metabolic rhythms have on influencing response to toxicity from physical stimuli, industrial toxins and therapeutic agents. Among those that have been, or currently are being investigated include: irradiation, paraquat, urethane, malathion, mercuric chloride, insulin, glucagon, epidermal growth factor (EGF), somatostatin, ACTH, and gastrin. The toxicity response in mice to all has been shown to be circadian-stage dependent. Moreover, some of the above polypeptides stimulate RNA and DNA synthesis in a number of tissues including the alimentary canal (EGF, insulin and gastrin) whereas others are predominately inhibitory (glucagon, somastatin, and ACTH), again all responses have been found to be circadian-stage dependent.
The aim of the present application is to continue such studies, but also, to determine if the chronobiological findings already gained can be used to reduce overall toxicity. The model chosen has been cell proliferation in certain regions of the intestinal tract, which also undergoes remarkable circadian variation. Can the fact that fasting, beginning at a certain circadian stage, for a span of 36 hours or less reduce the fraction of proliferating cells and thus be used to protect the gut from damage brought about by: (1) a physical agent such as irradiation which affects the mitotic spindle or (2) a chemical agent such as cytosine arabinoside, which specifically interfers with DNA synthesis? Morever, will any of the above mentioned peptides, when given before, simultaneously, or subsequent to either a physical or chemical induced injury protect different regions of the gut from damage or enhance repair? Another objective is to gain insight into the mechanism of action of EGF by exploring its effect at the level of the EGF cell surface receptor and EGF induced cell membrane protein phosphorylation in the gut of normal adult mice and those treated with irradiation. These studies have relevance for industrial toxicology, gastroenterology, immunology, and endocrinology.
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