Project Summary/Abstract Benign prostatic hyperplasia (BPH) is a progressive condition in aging men that is characterized by the enlargement of the periurethral regions of the prostate gland. An estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. BPH is often accompanied by lower urinary tract symptoms (LUTS). BPH is rarely fatal, but may cause serious life-threatening complications such as acute urinary retention if left untreated. However, molecular mechanisms of BPH initiation and progression remain incompletely understood. The lack of understanding of these mechanisms is a barrier to improved treatment. BPH is a heterogeneous disease that results from nonmalignant proliferations of both the prostate epithelial and stromal compartments. The stromal nodules and the epithelial glandular nodules are the two typical nodules in BPH. Histological comparison of the stromal nodules with human fetal prostate stroma revealed that the ontogenetic processes of fetal prostate stroma (a transition from immature mesenchymal phenotype to fibroblastic, fibromuscular, and ultimately smooth-muscular phenotype) are recapitulated in the development of the BPH stromal nodules. This observation supports a theory of embryonic “reawakening”, which proposes that improper reactivation of embryonic signaling like FGFs attributes to initiation and progression of these stromal nodules. Formation of glandular nodules is suggested to develop as a result of stromal hyperplasia and deregulated stromal-epithelial interaction. But the underlying molecular mechanisms for glandular nodules have not been defined definitively. Our preliminary study shows that the Wnt signaling is active in prostate stromal cells and is capable of regulating the prostate epithelial stem cell activity. The goal of this application is to use a combination of molecular and cellular biological approaches, genetically engineered mouse models, and human BPH specimens to investigate how the Wnt signaling in prostate stromal cells is altered in BPH and how it affects BPH pathogenesis.