NIMBLE: Non-Invasive Markers of Bladder Deterioration

NIMBLE：膀胱恶化的非侵入性标志物

• 批准号: 10316791
• 负责人: Rosalyn M Adam
• 金额: $ 58.28万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-06 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316791
• 关键词: Anti-Cholinergics; Biological Markers; Bladder; Bladder Tissue; Catheterization; Child; Chronic Kidney Failure; Clinical; Clinical Management; Complement; Detection; Deterioration; Development; Dysmyelopoietic Syndromes; Evaluation; Gold; Human; Interobserver Variability; Intervention; Kidney; Lead; Longitudinal cohort; Lower urinary tract; Mass Spectrum Analysis; Modeling; Monitor; Neurogenic Bladder; Obstruction; Operative Surgical Procedures; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Population; Prognostic Marker; Prospective cohort; Proteins; Proteome; Proteomics; Protocols documentation; Rattus; Renal function; Risk; Rodent; Sampling; Signal Transduction; Spinal Dysraphism; Structure; Testing; Time; Tissues; Ureteropelvic junction obstruction; Urinary tract; Urinary tract infection; Urine; Urodynamics; base; biomarker panel; cohort; improved; insight; intravesical; patient population; postnatal; prenatal; preservation; pressure; prospective; renal damage; repaired; response; tertiary care; treatment response; urinary; urologic

Project Abstract Neurogenic bladder from congenital myelodysplasia (Spina Bifida) presents lifelong challenges in bladder management. Even with improved clinical management up to 50% of patients with SB are at increased risk for development of chronic kidney disease associated with urologic complications of neurogenic bladder. Bladder management for patients with neurogenic bladder comprises catheterization to promote emptying, medication to decrease intravesical pressures and inhibit detrusor overactivity, and regular monitoring of bladder function by urodynamics (UDS). If conservative therapy fails, patients may undergo surgical intervention to enhance capacity and reduce intravesical pressure to minimize upper tract damage. Regardless, controversy exists over the best management protocol for the neurogenic bladder. UDS is considered the gold standard for evaluation of lower urinary tract function and the impetus for intervention. However, UDS is invasive, expensive, subject to substantial inter-observer variability and not routinely available beyond tertiary care centers. The availability of a quantitative, non-invasive approach to signal bladder changes that serve as a harbinger of renal deterioration would advance clinical management of this patient population significantly. Notably, no such markers have been validated prospectively as independent markers of functional bladder deterioration. In preliminary studies, we have identified a panel of urine biomarkers enriched in urine from two models of neurogenic bladder (human and rodent), but not detected in kidney urine from human patients with ureteropelvic junction obstruction. This, together with their detection in bladder tissue from rats with neurogenic bladder strongly suggests that this unique panel reflects pathological bladder wall remodeling as opposed to renal damage. Based on these observations we hypothesize that our Non-Invasive Markers of Bladder Deterioration (NIMBLE) represent prognostic markers of deterioration in bladder function in neurogenic bladder patients. We believe that these markers may also serve as early predictors of upper tract damage in this population. We will test the hypothesis with the following aims: Aim 1. Determine the association between bladder-enriched urine biomarkers and functional parameters in a well characterized prospective cohort of children with neurogenic bladder. Aim 2. Investigate bladder-enriched urine biomarkers, their association with function and their response to treatment in a longitudinal cohort of children and rodents with neurogenic bladder. In each aim we will use mass spectrometry-based proteomics to quantify our unique panel in sample cohorts with neurogenic bladder, determine their association with functional UDS and their response to pharmacological intervention. We will also profile the remaining urinary proteome to refine the biomarker panel. At the end of the project we will know the extent to which our NIMBLE panel reflects functional deterioration of the neurogenic bladder and how it could be implemented clinically to improve management of SB patients.

项目摘要 先天性骨髓增生异常（脊柱裂）引起的神经源性膀胱给膀胱带来终生挑战 管理。即使临床管理有所改善，仍有高达 50% 的 SB 患者面临更高的风险 与神经源性膀胱泌尿系统并发症相关的慢性肾脏疾病的发展。膀胱 神经源性膀胱患者的治疗包括插管以促进排空、药物治疗 降低膀胱内压并抑制逼尿肌过度活动，并定期监测膀胱功能 尿动力学（UDS）。如果保守治疗失败，患者可能会接受手术干预以增强能力 并降低膀胱内压力以尽量减少上尿路损伤。无论如何，对于最佳方案仍存在争议 神经源性膀胱的管理方案。 UDS 被认为是评估较低的黄金标准 尿路功能和干预的动力。然而，UDS 是侵入性的、昂贵的、受 观察者之间存在很大的差异，并且在三级护理中心之外通常无法获得。的可用性 定量、非侵入性方法来发出膀胱变化信号，作为肾功能恶化的先兆 将显着推进该患者群体的临床管理。值得注意的是，目前还没有这样的标记 前瞻性地验证其作为功能性膀胱恶化的独立标志物。 在初步研究中，我们从两个模型中鉴定出一组富含尿液的尿液生物标志物 神经源性膀胱（人类和啮齿动物），但在人类患者的肾尿中未检测到 肾盂输尿管连接部梗阻。这，连同他们在神经源性大鼠膀胱组织中的检测 膀胱强烈表明，这个独特的面板反映了病理性膀胱壁重塑，而不是 肾损伤。基于这些观察，我们假设我们的膀胱非侵入性标记 恶化 (NIMBLE) 代表神经源性膀胱功能恶化的预后标志 膀胱患者。我们相信这些标记物也可以作为上尿路损伤的早期预测因子。 这个人口。我们将通过以下目标来检验假设： 目标 1. 确定之间的关联 充分表征的前瞻性队列中富含膀胱的尿液生物标志物和功能参数 患有神经源性膀胱的儿童。目标 2. 研究富含膀胱的尿液生物标志物及其与 患有神经源性膀胱的儿童和啮齿类动物的功能及其对治疗的反应。 在每个目标中，我们将使用基于质谱的蛋白质组学来量化样本队列中我们独特的组 神经源性膀胱，确定它们与功能性 UDS 的关联及其对药理学的反应 干涉。我们还将分析剩余的尿液蛋白质组，以完善生物标志物组。结束时 项目中我们将了解我们的 NIMBLE 面板在多大程度上反映了神经源性功能退化 膀胱以及如何在临床上实施以改善 SB 患者的管理。