PROJECT SUMMARY AND ABSTRACT Age-related benign enlargement of the prostate gland (BPH) and associated lower urinary tract symptoms (LUTS) is the most common urologic condition in aging men affecting 70% of men over the age of 60. Despite initial success of therapies aiming to treat LUTS, these interventions are long -term, expensive, and discontinuation results in recurrent symptoms. Identifying and incorporating new therapeutic strategies f or clinical use to effectively treat BPH is necessary. Recent data from our lab and others has implicated stem cell transcription factor SOX2 in prostate regeneration pathways that play a role in prostate enlargement during BPH. SOX2 is highly expressed in BPH tissue and a lineage tracing experiment showed a SOX2-positive cell population survives prostate involution and can derive SOX2-negative luminal epithelial cells during prostate regeneration. Despite this evidence that SOX2 contributes to prostate gro wth/regeneration, pharmacologically targeting SOX2 expression in this context has not been explored. Data from a recent drug screening experiment, single cell RNA-seq, and mining of meta-data implicate IGF1R signaling as an upstream regulator of SOX2 transcription. Unpublished data shows a reduction of SOX2 transcript and protein after IGF1R inhibition. Based on these unpublished results, we hypothesize that SOX2 is necessary for prostate regeneration and that decreasing SOX2 expression through inhibition of IGF1R will prevent prostate regeneration and improve current therapeutics for BPH. The overall objectives for this proposal will address this hypothesis experimentally utilizing new model systems and technology and provide training and professional development support to advance the candidate’s career as an independent investigator. Addressing the hypothesis will utilize the following specific aims: 1) determine the impact of SOX2 in prostate epithelial cell survival and prostate enlargement and lower urinary tract dysfunctions of symptomatic BPH, and 2) delineate the mechanism for the reduction of SOX2 expression after IGF1R inhibition. To accomplish the first aim, prostate epithelial cell survival will quantified in vitro after IGF1R inhibition. To assess clinical relevance, a mouse model for symptomatic BPH will be utilized to assess prostate enlargement and voiding symptoms following IGF1R inhibition. To achieve the second aim, a proteome profiler, Western blotting, and siRNA will be utilized to interrogate the mechanism mediating the IGF1R/SOX2 regulatory pathway. To accomplish the proposed career development objectives, the candidate will 1) establish unique research position by developing technical skills in BPH-LUTS model systems and drug design and development, 2) cultivate skills necessary to facilitate a career as an independent researcher including formal training in mentorship and grant writing, and 3) strengthen research communication skills and network in the field of benign urology. Th...