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

男性尿道狭窄疾病（USD）可由创伤（如爆炸或骑跨伤）、感染、 炎症或医源性/特发性病因。USD产生排尿和储存相关的尿 并发症，可损害膀胱，然后最终损害肾功能。在退伍军人中，共有 在5年内为USD进行了92，448例手术。在经尿道和开放手术干预中， 大多数退伍军人（>95%）接受非手术经尿道介入治疗USD。这些非手术 干预措施并不总是成功的。因此，目前使用的非手术干预措施并不 不仅无效，而且已知会使手术介入结果复杂化。尿道损伤分析 疤痕组织显示尿道上皮和周围海绵体的纤维化增加。我们 初步研究证实了这些发现，并进一步表明，反复经尿道介入治疗， 例如经尿道扩张术（TUD）增加了瘢痕形成。如尿道狭窄的瘢痕组织 在患者中，瘢痕形成是由纤维化网络的上调介导的。 我们假设（i）尿液微生物组可能通过改变粘膜渗透性发挥作用，（ii）增加 损伤后纤维化对尿道纤维化的分子机制有一个清楚的认识， 能够识别新的目标，以开发创新策略，以最终预防/治疗 这种混乱。我们研究的具体目的是确定：1）组织损伤增加的机制 重复经尿道干预后; 2）微生物组的作用和3）使用体外共培养的因果关系 问题研究我们将使用几种新的方法：1）纵向测量狭窄的发展， 使用非侵入性成像的退伍军人; 2）狭窄患者尿液/瘢痕组织的详细分析研究 来识别细胞和分子通路。这些评估还将包括微生物组的作用; 3）我们 将从干净的捕获尿液样本中分离细菌，并使用人类进行共培养实验， 尿路上皮细胞培养（HUCC）模型。拟议的研究将有助于（i）确定具有 粘附和侵入尿道粘膜细胞（尿道炎）、诱导纤维化或细胞（粘膜）能力 损伤和（ii）还涉及测试粘膜屏障保护策略。机械的见解，从这些 研究不仅将从分子水平上研究这一主题，还将揭示进一步研究的新靶点。 开发预防纤维化的治疗策略。因此，我们的建议在概念上是新颖的（ 微生物组）和创新（使用新的方法，干预措施和工具，如MR-UTE来研究 纤维化），为新疗法铺平了道路。这项研究具有很高的临床转化潜力（应用 新的诊断工具和抗纤维化干预措施的发展），以最大限度地恢复功能， 老龄化的退伍军人人口。

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 recovery in the aging Veteran population.