application) The prostate gland contributes to a significant portion of the disease burden involving American males due to the high prevalence and increasing incidence of benign prostatic hyperplasia (BPH) and prostate carcinoma in aging men. Prostate cancer now represents the second leading cause of cancer death in American men. The prevalence of BPH numbers in the tens of millions. Nonetheless, little is known about the molecular factors that contribute to the onset or progression of these diseases. A primary impediment for identifying relevant molecular factors has been the paucity of information regarding the mechanisms of normal prostate growth and differentiation. Few regulatory genes are known to be expressed specifically during prostate development or to be required for prostate function. One approach toward the identification of factors involved in prostate development involves the use of mouse models. The mouse has the significant advantage of having an extensive background of accumulated genetic knowledge. In addition, the mouse genetic program can be manipulated in the form of transgenic and gene deletion animals to provide insights for gene function. We hypothesize that the dysregulation of genes directing the normal development of the prostate gland influence the pathogenesis of prostate diseases including BPH and malignancy.
The specific aims of this proposal are to:
Aim 1. To establish a virtual and physical cDNA clone archive representing developing, mature, and diseased mouse prostate.
Aim 2. To identify specific stromal and epithelial factors responsible for the directed development of mouse prostate.
Aim 3. To analyze the expression profiles of prostatic tissues derived from Nkx3.1 and p27Kipl knockout mice and determine their genetic interactions. The accomplishment of these aims will provide a genomics-based resource that defines cell type specific gene expression profiles associated with stages of normal development and neoplastic prostate growth.
