The objective of this grant application is to identify and characterize prostatic epithelial stem cells in order to gain insights into the mechanisms underlying the aberrant proliferative processes of benign prostatic hyperplasia (BPH) and prostatic carcinoma. The prostatic ducts are comprised primarily of basal cells and secretory luminal cells and the morphology and function of the prostatic ducts varies considerably along the distal-proximal axis. In an adult animal, proliferation takes place in the distal region of the ducts and apoptosis occurs mainly in a proximal location. The hypothesis to be tested in this application is that a small number of slow-cycling, quiescent stem cells are located in the basal cell layer at the tips of the distal ducts. These stem cells give rise to the rapidly dividing, progenitor, transit-amplifying cells, that migrate to the intermediate region of the ducts, where they become functionally mature, and secrete prostatic products. The cells finally migrate to the proximal region, where they senesce and die. This hypothesis will be tested in three series of experiments that exploit two important properties of stem cells, namely their high proliferative and their slow-cycling, quiescent behavior in vivo. The first experiments will determine whether the distal region of the duct contains the cells with the greatest proliferative potential using in vitro and in vivo assays. The second series of experiments will determine whether the slow- cycling stem cells are located in the basal cell layer at the tips of the distal region of the ducts, using in vivo 3H-thymidine labeling procedures. The third series of experiments will determine whether the histological distribution of slow-cycling cells is conserved in human prostate; this will be done by localizing 3H-thymidine label-retaining cells in human prostatic tissues maintained in vivo and in athymic mice. These experiments will locate and characterize the prostatic epithelial stem cells. This is essential for elucidating the mechanisms involved in aberrant prostatic cell proliferation.
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