Investigation of Urethral Dysfunction in Female Urinary Incontinence

Project Summary This proposal outlines a detailed training plan for the surgeon-scientist candidate to become an independent investigator. The proposal highlights the candidate’s research and career development plans to study female urethral aging and urinary incontinence (UI). UI is highly prevalent in women, rises with age, and costs~$10 billion annually. The current UI treatments leave up to 57% of the treated females with incontinence. Urethral failure is a key cause of UI, yet it is not addressed in any current UI treatments. Urethral function declines 15% per decade with aging. As such, this research aims to address the current knowledge gaps by unraveling the molecular changes in aging female urethral striated muscle and then translating the findings into potential treatments for urethral dysfunction. The candidate’s recent publication examined the impact of aging on the mouse urethra and found aged mice, like elderly females, exhibited notably reduced functional leak point pressure, significant loss of striated muscle and elastin, and increased fibrotic connective tissue compared to young mice. Gene expression profiling revealed the upregulation of extracellular matrix remodeling (e.g., Adamt5) and fibrogenic (e.g., Ctgf) genes in aged urethral tissues. Immunofluorescence staining and RNAscope analysis displayed an increased population of Pdgfrα+/Ly6a+ fibro-adipogenic progenitors (FAPs) cells expressing Ctgf in the striated muscle layer of aged mouse urethra compared to its younger counterparts. These findings suggest a novel mechanistic hypothesis that aged urethral tissue striated muscle dysfunction is attributed to increased fibrosis due to altered FAP cells that secrete factors, such as Ctgf, and that targeting Ctgf may result in the improvement of urethra function. To determine these mechanisms, the candidate will conduct a mouse and human urethra study (Aim 1) to identify changes in the transcriptome of FAP cells across three life stages of the female urethra. The proposed research also aims to determine the impact of Ctgf in age-related fibrotic urethral muscle dysfunction (Aim 2). This work will result in a deeper understanding of age-related urethral tissue dysfunction, and the potential to inform translation into the clinical setting. Through a rigorous mentorship and didactic plan, the candidate will 1) gain skills in analyzing and interpreting next-generation sequencing data (Aim 1) and 2) develop a genetically modified mouse model for understanding urethral failure (Aim 2), and ultimately evaluate potential drug treatments for UI (future). The candidate has assembled a robust and multi-disciplinary mentor team, developed a well-defined career development plan, and is provided phenomenal support from the UCI Department of Urology and the UCI Physician-Scientist Training program. This support and the rigorous training plan will ensure the PI achieves the proposed scientific goals proposed and is well-prepared for a successful, independent research career in investigating urinary tract dysfunction and UI.