Cancer remains the second leading cause of death in the United States. Advances in our understanding of neoplastic progression have provided new targets for intervention which can be utilized as smart assays for drug discovery. Natural products or compounds modeled on them have found significant utility in the treatment of cancer. In this proposal we seek to substantiate our hypothesis that actinomycetes which live in association with deep-sea invertebrates have undergone a unique evolution which in turn provided them with unique biosynthetic capabilities. This genetic information can be extracted and recombinant clones which express both the native genome and novel pathways derived from combinatorial biology can be produced. These clones will produce a diverse library of compounds for cancer drug discovery using target based assays. The project will be carried out in collaboration with the Sherman group from the University of Minnesota (Project 2) who will conduct combinatorial biology studies using DNA from HBOI originated isolates and Novartis Pharmaceutical Corporation (Project 3) who will carry out assays on extracts from clones which incorporate actinomycete biosynthetic gene sequences. Active actinomycete derived clones generated by Minnesota will be chemically deconvoluted at HBOI. The specific goals of the HBOI research project will be to: 1. Provide a diverse set of actinomycetes to Project 2 (U. of Minnesota) for cosmid preparation of native genome sequences and combinatorial biology studies. [Years 1-5 respectively: 60, 80, 60, 40, 40 isolates/year] 2. Using selective media/conditions, isolate additional actinomycete strains from deep water marine invertebrates for use in years 2-5 of the project. 3. Ferment active Streptomyces venezuelae clones derived from actinomycete DNA and carry out bioassay guided purification and structure elucidation of the active components.
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