Identification of Urinary Biomarkers for Stent Associated Symptoms in Humans

人类支架相关症状的尿液生物标志物的鉴定

• 批准号: 10798370
• 负责人: Dirk Lange
• 金额: $ 10万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-20 至 2024-05-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10798370
• 关键词: Accounting; Adolescent; Adult; Affect; American; Analytical Chemistry; Animal Model; Automobile Driving; Award; Biological Markers; Bypass; Capillary Electrophoresis; Complication; Data; Diabetes Mellitus; Dinoprostone; Disease; Enrollment; Environment; European; Event; Family suidae; Functional disorder; Goals; Health Expenditures; Human; Hydronephrosis; Impairment; Incidence; Individual; Inflammation; Inflammatory; Intervention; Kidney Calculi; Knowledge; Legal patent; Life; Mass Spectrum Analysis; Methods; Molecular; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Obstruction; Operative Surgical Procedures; Outcome; PTGS2 gene; Pain; Pain intensity; Pain interference; Participant; Pathogenicity; Pathway interactions; Patients; Peristalsis; Physiology; Postoperative Period; Prevalence; Quality of life; Recommendation; Recurrence; Reporting; Research; Sampling; Severities; Signal Transduction; Smooth Muscle; Stents; Stretching; Symptoms; Testing; Translating; United States; Ureter; Ureteral obstruction; Ureteroscopy; Urinary Calculi; Urine; Urology; Work; associated symptom; biomarker discovery; biomarker identification; biomarker validation; candidate identification; candidate marker; clinical epidemiology; cohort; experience; human morbidity; improved; ionization; longitudinal course; new therapeutic target; novel therapeutics; porcine model; predictive modeling; prevent; prospective; symptomatic improvement; targeted treatment; therapy development; urinary; urologic

(PLEASE KEEP IN WORD, DO NOT PDF) Ureteral stents placed after ureteroscopy to remove kidney stones cause significant morbidity, with most patients with an indwelling stent reporting impaired quality of life, pain, and urinary symptoms affecting their everyday life. A critical barrier to developing new treatments to improve symptoms caused by ureteral stents is a lack of understanding of how molecules in the urine contribute to mechanisms and patient experiences after ureteroscopy. Here, we build on our recent discoveries that stent-induced ureteral smooth muscle dysfunction, cessation of peristalsis, and resultant hydronephrosis are driven by stretch-induced inflammation of the ureter. We will leverage our analytical pipeline that identified prostaglandin E2 (PGE2) and 1-methylnicotinamide (1-MNA) as biomarkers for stent-induced ureteral inflammatory changes and dysfunction in pigs. We have an interdisciplinary team that is uniquely poised to discover and validate urinary biomarkers of stent symptoms by combining expertise in using analytic chemistry, ureteral physiology, and clinical epidemiology. The proposed research tests the central hypothesis that that indwelling ureteral stents trigger similar mechanisms in humans and that at least PGE2 and 1-MNA are urinary biomarkers for stent-associated ureteral dysfunction and symptoms in humans. In doing so, the proposed studies will identify pathways that could be targets for novel therapeutics to prevent stent symptoms. In this proposal, we generate key preliminary data using data and urine samples from 50 of the 484 adolescent and adult participants who underwent ureteroscopy with ureteral stent placement and enrolled in the Study to Enhance Understanding of sTent-associated Symptoms (STENTS) conducted by the NIDDK-supported Urinary Stone Disease Research Network. In Aim 1, we determine the association between PGE2 and 1-MNA and stent symptoms. We will evaluate the association between these putative biomarkers in pre-operative urine, and the course of patient-reported pain intensity, pain interference, and urinary symptoms after ureteroscopy with stent placement. In Aim 2, we will expand the list of urine biomarkers using our untargeted analytical approach to quantify and identify unknown biomarkers for ureteral obstruction and stent-associated symptoms. The proposed work provides key preliminary data validating known and new urinary biomarkers for stent-associated ureteral inflammatory changes and dysfunction in humans. Once validated in a smaller cohort, their association with stent-associated pain and discomfort can be further validated in a larger patient cohort and incorporated into existing predictive models for stent-complications to identify patients more likely to develop severe symptoms. This will form the basis of a subsequent R01 application.

（请保持言语，不要PDF） 放置输尿管镜检查以去除肾结石的输尿管支架会引起明显的发病率，大多数具有留置支架报告的患者的生活质量，疼痛和尿症状受损，影响其日常生活。开发新治疗方法以改善输尿管支架引起的症状的关键障碍是缺乏了解尿液中分子在输尿管镜检查后如何促进机制和患者体验的情况。 在这里，我们建立在最近的发现的基础上，即支架引起的输尿管平滑肌功能障碍，蠕动的停止以及由此导致的肾结通症是由输尿管的拉伸诱发的炎症驱动的。我们将利用分析管道确定前列腺素E2（PGE2）和1-甲基二甲酰胺（1-mNA）作为支架引起的输尿管炎症变化和猪功能障碍的生物标志物。我们拥有一个跨学科团队，该团队唯一准备通过结合使用分析化学，输尿管生理学和临床流行病学方面的专业知识来发现和验证支架症状的尿生物标志物。拟议的研究检验了一个中心假设，即留置输尿管支架触发人类的相似机制，并且至少PGE2和1-MNA是尿生物标志物，用于支架相关的输尿管功能障碍和人类的症状。在此过程中，拟议的研究将确定可能是预防支架症状的新型治疗剂的靶标。在此提案中，我们使用来自484名青少年和成年参与者中的50名数据和尿液样本生成关键的初步数据，他们接受了输尿管镜检查，并进行了输尿管镜，并参与了研究，以增强对NIDDK支持的尼德克（NIDDK）支持的尿液尿液结石研究网络的理解。在AIM 1中，我们确定PGE2和1 mNA和支架症状之间的关联。我们将评估这些假定的生物标志物在术前尿液中的关联，以及输尿管镜检查和支架放置输尿管镜检查后患者报告的疼痛强度，疼痛干扰和泌尿症状的过程。在AIM 2中，我们将使用我们未经定程的分析方法来扩展尿液生物标志物的列表，以量化和识别输尿管阻塞和支架相关症状的未知生物标志物。拟议的工作提供了关键的初步数据，可验证已知和新的尿液生物标志物，用于与人类相关的输尿管炎症性变化和功能障碍。一旦在较小的队列中进行了验证，就可以在较大的患者队列中进一步验证它们与支架相关的疼痛和不适的关联，并将其纳入现有的预测模型中，以确定患者更有可能出现严重症状。这将构成随后的R01应用程序的基础。