Although our understanding of the molecular mechanisms that underlie early development of the vertebrate embryo has advanced dramatically, there has been much less progress in clarifying the processes that orchestrate the formation of the elaborate structures that make up many of the body's organ systems. Elucidating early steps in genitourinary tract development and subsequent steps in determining and differentiating prostate cell lineages is expected to identify genes important in prostate diseases such as benign prostatic hyperplasia and prostate cancer. Cancer of the prostate is the most commonly diagnosed cancer in males in the United States and is the second leading cause of cancer death in men. Many risk factors for human prostate cancer have been proposed, however, its exact etiology is still largely unknown. Since a wide variety of genetic and genomic approaches are possible in the mouse, systematic assess gene expression of the developing mouse prostate will provide an extremely valuable database for research using this species. In turn, genetic studies in mice are likely to further our understanding of the mechanism of human prostate cancer development. We propose to systematically catalog cell-specific patterns of gene expression in mouse prostate. (1) We will quantify genes that are expressed in the stroma, basal and columnar epitheial cells of the mouse ventral, lateral, dorsal and anterior prostate by microSAGE. A total equal to or greater than1,350,000 transcripts will be determined, with which we will have a 96.6% chance to identify genes that are expressed at 1 copy/cell level. (2) We will compare the gene expression profile between the stroma and epithelial cells in different anatomical locations of the mouse prostate (a total of 75 comparisons). We will confirm SAGE results by real-time PCR quantitation. We will post results on our web site so that the data are available to the entire research community. (3) We will compare genes that are differentially expressed during the human prostate tumor progression from normal to BPH, PIN, carcinoma and bone metastases to genes that are expressed in mouse prostate to identify mouse homologues/orthologues. Our study will provide the first comprehensive mouse prostate gene database. More importantly, we will provide a list of candidate genes that are likely to be involved in prostate tumor progression. The data should be a rich, valuable resource for devising future genetic targeting, animal modeling and other experiments related to developmental biology in general and prostate cancer in particular.

R01ES011124

2000-09-30

2005-05-31