This is a new research component of a competitive renewal application to continue to explore the isolation of natural product inhibitors of carcinogenesis. In this project, new inhibitors will be sought from deep ocean-derived microorganisms using methods recently established. The specific goals of the project are: - To isolate new, deep ocean sediment-derived microorganisms from US locations in the Caribbean, the Gulf of Mexico, the Pacific Coast of the US (including Alaska), Hawaii and Guam. To identify these organisms, when appropriate, by phylogenetic methods using 16S rRNA gene sequence alignment for bacteria, and possibly 18S rRNA gene sequence alignments for fungi. - To cultivate at least 3,000 diverse deep sea microorganisms for extract screening in the Program bioassays. Since each culture is grown under 4 different conditions, 12,000 testing samples will be generated over the 5-year grant period. - To isolate, by bioassay-guided fractionation, new molecules with significant activity in the cyclo-oxygenase 1 and 2, quinone reductase, aromatase, cell differentiation, induction of apoptosis, and reporter gene based (ERE, NF-kB, PPAR, ARE) bioassays. - To support the pharmaceutical development of new marine microbial inhibitors of carcinogenesis by mass scale cultivation to supply up to gram quantities of new molecules for preclinical pharmacology. - To participate by supplying starting material compounds for structure modification or semisynthesis. - To undertake strain improvement, mutation and culture modification experiments to produce related metabolites when structural novelty and bioactivity profiles warrant.
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