ABSTRACT – PROJECT 1 Benign Prostatic Hyperplasia (BPH) is the benign enlargement of the prostate gland that occurs in older men, obstructing bladder outflow. The resultant lower urinary tract symptoms, such as urgency, frequency and incomplete emptying, have considerable morbidity, and carry annual healthcare costs in the Billions. Current BPH treatments are not very effective because the drugs target normal prostate physiology but not BPH pathophysiology, which is still poorly understood. New disease-targeted therapies will require a more detailed knowledge of BPH pathogenesis. In genomic studies of BPH clinical samples, we discovered a stromal gene signature that correlated with BPH symptoms, and an enrichment of fibroblasts overexpressing signaling proteins BMP5 and CXCL13. Fibroblast BMP5 enhanced prostate epithelial proliferation and drove gene expression profiles to mimic BPH tissue. From these data, we hypothesize that BPH is driven (at least in part) by pathogenic fibroblast cell subset(s), where defining those subsets will provide important new opportunities for disease targeted therapies. Towards that goal, the proposed studies aim to Define the fibroblast subsets in BPH versus normal prostate; Determine the key interactions between BPH fibroblast subsets and prostate epithelium that drive prostate enlargement; and Distinguish between BPH origins in embryonic re-awakening versus injury response. Study findings will provide new understanding of the contribution of prostate stroma to BPH pathogenesis, and identify new strategies for targeted treatment.