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

反复经尿道干预和进行性尿道狭窄疾病：机制阐明和新的干预策略

• 批准号: 10581375
• 负责人: MAHADEVAN Raj RAJASEKARAN
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581375
• 关键词: Adhesions; Affect; Aging; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bladder; Butyrates; Cell Culture Techniques; Cells; Cicatrix; Clinical; Coculture Techniques; Consensus; Corpus Spongiosum; Culture-independent methods; Cystoscopy; Data; Development; Disease; Disease Progression; Epithelium; Etiology; Evaluation; Extravasation; Failure; Fibrosis; Functional disorder; Human; Iatrogenesis; Impaired Renal Function; In Vitro; Infection; Inflammation; Inflammatory Response; Injury; Intervention; Invaded; Knowledge; Lower urinary tract; Magnetic Resonance Imaging; Measurement; Mediating; Medical; Metagenomics; Methods; Modality; Modeling; Molecular; Monitor; Mucous Membrane; Myofibroblast; Operative Surgical Procedures; Outcome; Pathogenicity; Pathologic; Pathway interactions; Patient Recruitments; Patients; Permeability; Prevention strategy; Procedures; Recovery of Function; Recurrence; Recurrent disease; Reporting; Ribosomal RNA; Role; Sampling; Seminal; Severities; Severity of illness; Shotguns; Specimen; Stretching; Surgical complication; Surgical incisions; Taxonomy; Testing; Therapeutic; Therapeutic procedure; Tight Junctions; Time; Tissues; Trauma; Up-Regulation; Urethra; Urethral Stricture; Urinary Microbiome; Urinary tract; Urine; Urologic Diseases; Urothelial Cell; Urothelium; Veterans; cell injury; clinical translation; clinically relevant; cytotoxicity; diagnostic tool; disease phenotype; experimental study; fibrogenesis; healing; imaging modality; improved; innovation; insight; male; microbial; microbiome; microbiome signature; microbiota; microorganism; military veteran; non-invasive imaging; novel; novel diagnostics; novel strategies; novel therapeutics; older men; older patient; preservation; prevent; prophylactic; relapse prevention; repaired; surgery outcome; therapy development; tool; treatment strategy; urinary

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.

雄性尿道狭窄疾病（USD）可能是由于爆炸或跨损伤，感染， 炎症或医源性/特发性病因。美元产生排尿和储存相关的尿液 并发症，会损害膀胱，然后最终损害肾功能。在退伍军人中，总共 在5年内进行了92,448项程序。尿道和开放手术干预措施的 大多数退伍军人（> 95％）接受了USD的非手术性尿道干预措施。这些非手术 干预措施通常不会永久成功。因此，当前使用的非手术干预措施不是 只有无效，但也知道使手术介入的结果复杂化。尿道分析 疤痕组织已显示尿道上皮和周围海绵的纤维化增加。我们的 初步研究证实了这些发现，并进一步证明了重复的尿道干预 例如经尿道扩张（TUD）增加了疤痕。如狭窄的尿道疤痕组织所见 患者，疤痕是通过纤维纤维网络上调介导的。 我们假设（i）尿微生物组可能通过改变粘膜渗透性和（ii）增加而发挥作用 受伤后的纤维化。对尿道纤维化涉及的这些分子机制的清晰了解将 为了最终预防/治疗 这个疾病。我们研究的具体目的是确定：1​​）增加组织损伤的机制 反复进行尿道干预后； 2）微生物组的作用和3）利用体外共文化的因果关系 研究。我们将使用几种新颖的方法：1）纵向测量狭窄的纵向测量 退伍军人使用非侵入性成像； 2）狭窄患者的尿液/疤痕组织中的详细分析研究 鉴定细胞和分子途径。这些评估还将包括微生物组的作用； 3）我们 会将细菌与清洁捕获尿液样本分离并使用人进行共培养实验 尿路上皮细胞培养（HUCC）模型。拟议的研究将有助于（i）确定具有的微生物组 粘附并侵入尿道粘膜细胞（尿路上皮）的能力，诱导纤维化或细胞（粘膜） 损坏和（ii）也测试粘膜屏障策略。从这些中获得的机械洞察力 研究不仅将从分子水平检查该主题，而且还会揭示新的目标以进一步 制定预防纤维化的治疗策略。因此，我们的建议在概念上都是新颖的（ 微生物组）和创新（使用新颖的方法，干预措施和MR-ut等工具来研究 纤维化），为新疗法铺平道路。这项研究具有临床翻译的高潜力（应用 新颖的诊断工具和抗纤维化干预措施的开发），以最大程度地恢复功能恢复 老化的退伍军人人口。