# Repeated Transurethral Interventions and Progressive Urethral Stricture Disease: Elucidation of Mechanisms and Novel Interventional Strategies

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

Urethral stricture disease (USD) in males can result from trauma such as blast or straddle injuries, infection,
inflammation, or iatrogenic/idiopathic etiologies. USD produces voiding and storage-related urinary
complications, which can damage the bladder and then ultimately impair renal function. In Veterans, a total of
92,448 procedures were performed for USD in 5 years. Of the transurethral and open surgical interventions, a
majority of Veterans (>95%) undergo non-surgical transurethral interventions for USD. These non-surgical
interventions are not often permanently successful. Thus, the currently used non-surgical interventions are not
only ineffective but also known to complicate surgical interventional outcomes. The analysis of urethral
scar tissue has shown increased fibrosis of the urethral epithelium and surrounding corpus spongiosum. Our
preliminary studies confirm these findings and further demonstrate that repeated transurethral interventions
such as transurethral dilation (TUD) increased scarring. As seen in urethral scar tissues from stricture
patients, scarring is mediated by upregulation of the fibrogenic network.
We hypothesize (i) urinary microbiomes may play a role by altering mucosal permeability and (ii) that increased
fibrosis after injury. A clear understanding of these molecular mechanisms involved in urethral fibrosis would
enable identification of novel targets for development of innovative strategies in order to eventually prevent/treat
this disorder. The specific aims of our studies are to determine: 1) mechanisms of increased tissue damage
after repeated transurethral interventions; 2) the role of microbiomes and 3) causality using in vitro co-culture
studies. We will use several novel approaches: 1) longitudinal measurement of stricture development in
Veterans using non-invasive imaging; 2) detailed analytical studies in urine/scar tissues from stricture patients
to identify cellular and molecular pathways. These evaluations will also include the role of microbiomes; 3) We
will isolate bacteria from clean catch urine specimens and perform co-culture experiments using human
urothelial cell culture (HUCC) model. The proposed studies will help to (i) identify the microbiomes that have
the ability to adhere to and invade urethral mucosal cells (urothelium), induce fibrosis or cell (mucosal)
damage and (ii) also to a test a mucosal barrier protection strategy. Mechanistic insights gained from these
studies will not only examine the topic from the molecular level, but also unravel novel targets for further
development of treatment strategies to prevent fibrosis. Thus, our proposal is both conceptually novel (role of
microbiomes) and innovative (uses novel approaches, interventions, and tools such as MR-UTE to study
fibrosis), paving the way for new therapies. This study has high potential for clinical translation (application of
novel diagnostic tools and development of anti-fibrotic interventions) to maximize functional ...

## Key facts

- **NIH application ID:** 10581375
- **Project number:** 1I01CX002401-01A2
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** MAHADEVAN Raj RAJASEKARAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10581375

## Citation

> US National Institutes of Health, RePORTER application 10581375, Repeated Transurethral Interventions and Progressive Urethral Stricture Disease: Elucidation of Mechanisms and Novel Interventional Strategies (1I01CX002401-01A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10581375. Licensed CC0.

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