Project Summary African American (AA) men have an increased risk for both prostate cancer (PCa) incidence and mortality. Although socio-economic status and other environmental and cultural factors likely contribute to this racial disparity, emerging evidence has shown an important role of genetic and epigenetic factors in the pathogenesis of AA PCa. Androgens and the androgen receptor (AR)-mediated signaling pathways play a central role in prostate tumorigenesis. The AR is a ligand-induced transcriptional factor and contains an N-terminal transactivation domain (NTD). The NTD of human AR possesses polymorphic trinucleotide repeats, CAGs (cytosine, adenine, guanine), which codes for the polyglutamine (PolyQ) tract. The length of CAG repeats in the human AR gene has been shown to be inversely correlated with the risk of developing PCa, age of disease onset, and risk of advanced PCa at diagnosis. Intriguingly, AA men bear shorter CAG repeats significantly more frequently than Caucasian American (CA) men, linking the length of polyQ tracts to the pathogenesis of PCa in AA men. Additionally, a significant co-activation of the androgen and Wnt signaling pathways has been revealed in fast growing and early onset PCa, specifically enriched in AA PCa samples. Moreover, emerging evidence has shown a niche role of stromal AR to support prostatic epithelial oncogenesis. However, despite these intriguing findings and past scientific progress, the oncogenic role and related molecular mechanism for AR-mediated signaling pathways in PCa tumorigenesis, specifically in AA PCa racial disparity, remain elusively. One of the bottlenecks for these shortfalls is the lack of biologically relevant animal models that can recapitulate aberrant AR activation in promoting PCa development and progression, mimicking the situation in AA patients. To directly address this challenge, we propose a series of experiments using our new and relevant animal models, human PCa samples, single-cell RNA sequencing, and other advanced approaches to directly test our central hypothesis that aberrant activation of the AR bearing short polyQ tracts in both prostatic epithelia and stroma promotes PCa initiation, progression, and hormone refractoriness in AA patients. Successful completion of the proposed study should directly impact the current paradigms and lead to the development of new preventive and therapeutic strategies to improve clinical outcomes for AA PCa patients.