GENETIC MANIPULATION OF THE MOUSE PROSTATE GLAND

DESCRIPTION (Adapted from the applicant's abstract): The overall goal of the proposed work is to gain a better understanding of the gene products involved in abnormal human prostatic growth. The investigators plan to develop a transgenic model system that will allow the reproducible manipulation of the genetic activity of the mouse prostate gland. During the first phase of the project, the plan is to construct a series of chimeric genes by fusing various regions of promotor DNA from the rat ventral prostate C3 gene, the rat dorsal prostate probasin gene, or the Mouse Mammary Tumor Virus Ltr element to a eucaryotic reporter gene encoding beta galactosidase. These chimeric DNAs would then be microinjected into single-cell mouse embryos and the resulting transgenic mice studied to determine the tissue-specific expression pattern and the influence of androgenic steroids on the expression of B-gal in the mouse prostate gland. After identification of a promotor DNA that reproducibly directs high-level expression of the reporter gene in the mouse prostate, the investigators plan to substitute growth-influencing genes for the reporter then determine the effects of the genetic manipulations on the phenotype of the resulting transgenic mice. Chimeric genes will be designed to direct hyperexpression of c-myc, activated Ha-ras or basic fibroblast growth factor in the mouse prostate so these can be studied for their effects on prostatic development, growth rate and rate of oncogenesis. In addition, chimeric genes designed to express "antisense" RNA for these genes would be tested for their ability to suppress mouse prostate development and growth. Successful conclusion of this project will result in an animal model to assess the effect of a given gene product on prostate growth parameter. The investigators expect that the model will provide a novel and unique system to test anti-growth therapies for the treatment of human prostate diseases.