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

男性的尿路狭窄病可由冲击伤或骑跨伤、感染、 炎症，或医源性/特发性病因。市署制造尿液及储存尿液 并发症，可损害膀胱，最终损害肾功能。在退伍军人中，总共有 在5年内，共进行了92,448次手术。在经尿道和开放手术介入治疗中， 大多数退伍军人(&gt；95%)接受非手术治疗。这些非手术的 干预措施往往不会永久成功。因此，目前使用的非手术干预不是 不仅无效，而且已知还会使手术干预结果复杂化。关于尿路的分析 瘢痕组织显示尿道上皮和周围海绵体纤维化增加。我们的 初步研究证实了这些发现，并进一步证明，重复的经尿道干预 如经尿路扩张(TUD)增加瘢痕形成。从狭窄所致的尿路疤痕组织中可见 患者，瘢痕形成是通过纤维形成网络的上调而介导的。 我们假设(I)尿微生物群可能通过改变粘膜通透性而发挥作用，以及(Ii)增加 损伤后的纤维化。清楚地了解这些与尿路纤维化有关的分子机制将会 能够确定开发创新战略的新目标，以便最终预防/治疗 这种紊乱。我们研究的具体目的是确定：1)组织损伤增加的机制 2)微生物群的作用；3)体外共培养的因果关系 学习。我们将使用几种新的方法：1)狭窄发展的纵向测量 使用非侵入性成像的退伍军人；2)狭窄患者尿液/疤痕组织的详细分析研究 以确定细胞和分子途径。这些评价还将包括微生物群的作用；3)我们 将从干净的捕获尿液样本中分离细菌，并与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)识别具有 黏附和侵袭尿路粘膜细胞(尿路上皮)、诱导纤维化或细胞(粘膜)的能力 损害和(Ii)还测试一种粘膜屏障保护策略。从这些方面获得的机械洞察力 研究不仅将从分子层面研究这一主题，还将为进一步研究揭开新的靶点 制定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(角色 微生物)和创新(使用新的方法、干预和工具，如MR-UTE来研究 纤维化)，为新的治疗方法铺平了道路。这项研究具有很高的临床翻译潜力(应用 新的诊断工具和抗纤维化干预措施的开发)以最大限度地促进患者的功能恢复 退伍军人人口老龄化。

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.