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

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A series of projects are ongoing in the cyclooxygenase (COX) knockout mice. 1) Air pouchs have been successfully formed on the COX-1 and COX-2 knockout mice. Their responses to inflammatory agents (carrageenan and TPA) are being studied. Differences in the responses of the COX-1 and -2 animals have been observed in production of PGE2 and LTB4, and in the cells recruited to the site of inflammation. 2) Gastric ulceration induced by alcohol or NSAIDs in COX-1 knockout mice has been compared to that induced in the wild type mice. 3) COX-1 mice have been bred to FVB/N mice carrying the tg.ac transgenic ras oncogene. Contrary to expectations, the COX-1 deficient mice appear more susceptible to the development of skin papillomas following TPA promotion of the ras heterozygous/ COX-1 knockout homozygous animals and also following DMBA initiation/TPA promotion of COX-1 homozygous knockout animals that do not carry the tg.ac ras oncogene. The effects of NSAIDs on tumorigenesis will also be studied and compared to the effects of the knockouts. 4) COX-1 and COX-2 mice are being bred to APC (min) mice which are susceptible to spontaneous adenopolyposis of the colon. The effects of the knockouts on spotaneous colon carcinogenesis will be studied in the absence or presence of NSAIDs. 5) The COX-1 and COX-2 knockouts are being bred into the C57/BL6J and 129J inbred strains. These mice will provide a homogeneous genetic background for future studies and should lead to improved statistics in all studies.