MOUSE MODEL--TARGETED GENE KNOCK-OUT OF PROSTAGLANDIN SYNTHASE I AND II

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COX-1(-/-) mice are of normal health and show no obvious pathology. COX-1(-/-) pups are born in the expected ratio. Significantly, in COX-1(-/-) mice, COX-2 message is upregulated in some tissues and is greatly upregulated at the protein level in several tissues. Mechanistically, this upregulation must be compensatory and indicates a means of crosstalk between COX-1 and COX-2 which was previously unknown. COX-1(-/-) mice have reduced PGE-2 production by macrophages, reduced platelet aggregation and reduced inflammatory response to ertain chemicals; but susprisingly, NSAID induced gastric ulceration is about equal to COX-1(+/+) mice. COX-1(-/-) females have fertility/partuition problems dependent on the genotype of the male and/or pups. Studies of the COX-2 knock-out are at an earlier stage than the COX-1 mice; but are in progress both at NIEHS and UNC. By contrast to COX-1 mice COX-2(-/-) mice are generally unhealthy with 100% dying before 5 months of age (pathologies are being determined). Therefore, by utilizing these mice we can gain a better understanding of the inflammatory process in general, the specific roles of COX-1 and COX-2 in inflammatory diseases, as well as insight concerning the roles of COX-1 and -2 in the carcinogenesis process. Additionally, this knowledge will allow the design of better therapeutic and prophylatic drugs to treat inflammatory diseases.