Strand/Vezina Group

Project Description

Lower urinary tract dysfunction (LUTD) is nearly ubiquitous in men of advancing age and involves a dynamic interplay among the prostate, bladder and urethra. The cellular and molecular mechanisms of prostate enlargement are largely unknown. Furthermore, bladder dysfunction persists in a third of men after transurethral resection of the prostate, but the cellular basis of bladder remodeling and dysfunction are poorly understood. Contemporary single cell sequencing technologies could fundamentally revitalize our knowledge of LUTD as they have for other diseases. Unfortunately, most investigators are unable to access bladder, urethra and prostate from young and aged, disease-free males (controls) to leverage these technologies and determine how cellular behaviors change with age and disease. Moreover, the cost to deploy single cell sequencing makes a comprehensive examination of the lower urinary tract untenable for most investigators.

The proposed studies will conduct scRNA/scATAC-seq of the human prostate, urethra and bladder from young disease-free male organ donors and men of advancing age with clinically-defined BPH and detrusor overactivity. Disease-specific regulatory networks will be identified and linked to clinical phenotypes. A searchable database will be created to query processed data and request tissue specimens. The overarching goal is to eliminate barriers to primary human tissue research. For years, we have tried to test specific mechanistic hypotheses about LUTD without a thorough molecular and cellular characterization of the normal vs. diseased state. These foundational resources will generate new testable hypotheses about LUTD, lead to the creation of better animal models, and expand the diversity of investigators in LUTD research.

We will use single cell sequencing data that only we have already generated on the mouse bladder, urethra and prostate to inform our development of transgenic mice carrying cell-specific and inducible Cre recombinase in lower urinary tract stromal cell types. These new resources will enable researchers to test hypotheses arising from human LUT cell scRNA/scATAC-seq data. An innovative split-Cre approach, in which Cre recombinase fragments are driven from two independent gene promoters, will be used to ensure organ and cell specificity. Split-Cre mice will be used to trace the lineage of bladder, urethral and prostate stromal cells during clinically-relevant induction of LUTD. A genetic approach will be deployed to singly remove each cell type from the lower urinary tract to determine how it contributes to baseline urinary physiology and response to bladder outlet obstruction. Quantitative urinary voiding phenotypes from these mice will be linked via a database to single cell sequencing data, enabling investigators to formulate cause-and-effect hypotheses. Though the resources generated here will focus on male LUTD and control tissues to establish a controlled human experimental framework, the resource is scalable and in the future can expand to include tissues and research models relevant to female benign urologic diseases and urologic cancer.