Bedside to bench resources for lower urinary tract research

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Lower urinary tract dysfunction (LUTD) is a constellation of human-reported urinary indications, including urgency, intermittent and weak urinary stream, incomplete bladder emptying, and increased voiding frequency. A major cause of male LUTD is benign prostatic hyperplasia (BPH), which is medically managed with five alpha reductase inhibitors or alpha-adrenergic receptor antagonists. Neither drug reduces symptomatic progression by more than 34% and most of these elderly men have no option but surgery. Prostatic obstruction of urine flow can lead to bladder detrusor overactivity (DO), a poorly understood disease with largely ineffective therapeutic options. The medical management of LUTS due to prostate and bladder dysfunction has seen little improvement over the past 40 years because we have failed to capture the cell type-specific molecular alterations that would provide actionable therapeutic targets. This proposal will address fundamental barriers to deriving molecular mechanisms of human LUTD. In Aim 1 we will produce multi-omic data on cell type-specific molecular changes in human LUTD. We will link the data to a tissue repository managed with OpenSpecimen software, giving researchers searchable access to >3,000 clinically annotated normal and diseased human specimens. In Aim 2 we will engineer new mouse strains to achieve Cre expression in specific bladder, urethra, and prostate stromal cells. It is not possible with existing mouse strains to overexpress or knockout a gene in a bladder stromal cell without introducing the same genetic change in prostate and urethra, or vice versa. Accordingly, the unique contributions of prostate and bladder to urinary voiding cannot be isolated. We will overcome this problem by creating new mouse strains with selective inducible Cre expression in fibroblasts and smooth muscle. Finally, we will ensure that all resources are FAIR (Findable, Accessible, Interoperable, and Reusable) by incorporating all methods, tools, data and protocols into the NIDDK ATLAS Data Center. The proposed resources are significant because they establish foundational bedside to bench resources to generate and test hypotheses about LUTD mechanisms in human tissues and rationally designed mouse models.