application) This R-21 application is submitted in response to the RFA (DK00-015), """"""""Cell Specific Delineation of Prostate and Genitourinary Development."""""""" Although it is known that androgen influence on gene expression of cells in the mesenchyme are critical for differentiation of the prostatic epithelium, the molecular processes and cell interactions that lead to the tissue organization and the full cellular complexity of the mature gland are poorly understood. Our long-term goal is to understand the role of proteases in regulating development, function, and pathogenesis of diseases of the prostate gland. The objective of this application is to study cell surface proteolytic enzymes critical to prostate development because of their controlling roles in cell growth and cell-cell and cell-extracellular matrix interactions. The central hypothesis of this proposal is that there is a temporal dependent and cell type specific expression of metalloproteases of the matrix metalloprotease (MMP) and metalloprotease disintegrin (ADAM) families, and of other kinds of protease, controlling individual steps during prostate development. The rationale for this proposed research is that once we know the time in development of a cell type expressing a controlling protease, we can determine the regulation of the protease expression in normal. prostate development and potentially in neoplastic growth. In addition, these cell surface proteases can be tagged by antibodies or specific inhibitors for characterization and purification of individual cell types. The central hypothesis will be tested and objectives of the proposal accomplished by pursuing two specific aims: 1) determine the stage of prostate-development for expression of cell surface proteases, and 2) determine the cell types expressing individual cell surface proteases at specific stages of prostate development. The proposed work addresses several needs detailed in the RFA. It systematically assesses gene expression in specific cell types in the developing and adult mouse prostate. These are protease genes that are expected to be important in prostate development because they function at the cell surface in growth factor processing and modification of plasma membrane and extracellular matrix proteins that are critical in cell growth and cell-cell and cell-extracellular matrix interactions. Such outcomes will be significant because it is expected that this new knowledge will suggest novel protease targets important in prostatic neoplasia and the cell surface protease about can be used to develop methods (antibodies and/or immobilized inhibitors) to isolate the identified cell types for culture and development of cell lines.
