MOLECULAR MECHANISMS IN NEOPLASIA

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The overall goal of this project is the exploration and exploitation of the biology of retroviruses as a means to a deeper understanding of neoplastic change. The model system on which the majority of the proposed work is focused is the induction of lymphomas in the bursa of Fabricius of chickens by natural and genetically engineered retroviruses. Specific experiments are directed at exploring the role of specific oncogenes in the induction of the pre-neoplastic transformed follicle stage and in the progression from transformed follicles to more advanced neoplasms. Retroviral constructs bearing c-myc and ChBlym-1 genes will be prepared, evaluated in tissue culture systems and introduced into embryonic bursal stem cells by the technique of bursal transplantation. Preneoplastic lesions and advanced neoplasms induced by this methodology will be evaluated for the expression of the relevant oncogenes using nucleic acid and immunologic probes. The normal expression of these and other proto-oncogenes will be evaluated in bursal lymphocytes using a counterflow centrifugation technique to separate lymphocyte populations. In situ hybridization will be used to amplify results obtained by the physical separation technique. Evidence will be sought of physiological mitogenic stimulation of bursal lymphocytes during development. Proto-oncogenes other than c-myc, for example, c-fos which are normally activated by this process, and a number of other potentially interesting genes, will be tested for their effects in the bursal transplantation assay. Finally, an attempt will be made to develop retroviral constructs expressing anti-sense RNA which might be used to selectively inhibit oncogene expression in this in vivo system.