NIMBLE: Non-Invasive Markers of Bladder Deterioration

项目摘要 先天性脊髓发育不良神经原性膀胱(脊柱裂)对膀胱构成终生挑战 管理层。即使改善了临床管理，高达50%的SB患者也面临着更高的风险 慢性肾脏疾病与神经源性膀胱的泌尿系统并发症的发展。膀胱 神经原性膀胱患者的治疗包括导尿术促进排空，药物治疗 降低膀胱内压，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提高能力 并降低膀胱内压力，将上尿路损伤降至最低。无论如何，对于最好的人选存在争议 神经源性膀胱的治疗方案。UDS被视为评估LOWER的金标准 尿路功能及干预的动力。然而，UDS是侵入性的，昂贵的，受 观察者之间有很大的可变性，并且在三级护理中心之外不能常规获得。可提供的 定量、非侵入性方法检测作为肾脏恶化先兆的膀胱信号改变 将极大地促进这一患者群体的临床管理。值得注意的是，没有这样的标记被 前瞻性验证为功能性膀胱恶化的独立标记物。 在初步研究中，我们已经从两个模型中确定了一组富含尿液的尿液生物标志物。 神经源性膀胱(人和啮齿动物)，但在人类肾综合征患者的肾尿液中未检测到 肾盂输尿管连接部梗阻。这与在神经源性疾病大鼠的膀胱组织中检测到的它们一起 膀胱强烈提示，这个独特的面板反映了病理性的膀胱壁重构，而不是 肾脏受损。基于这些观察，我们假设我们的非侵入性膀胱标志物 神经源性患者膀胱功能恶化(灵活)是其预后指标 膀胱病患者。我们认为，这些标志物也可以作为上尿路损害的早期预测指标。 这群人。我们将通过以下目标来检验这一假设：目标1.确定 膀胱富集型尿液生物标志物和功能参数在一组具有良好特征的前瞻性队列中的研究 神经性膀胱的儿童。目的2.研究富含膀胱的尿液生物标志物及其与 神经原性膀胱的儿童和啮齿动物纵向队列的功能及其治疗反应。 在每个目标中，我们将使用基于质谱学的蛋白质组学来量化样本队列中我们独特的小组 神经原性膀胱，确定它们与功能性UDS的关系以及它们对药物的反应 干预。我们还将对剩余的尿蛋白质组进行分析，以完善生物标志物面板。在结束时， 我们将知道我们的灵活面板在多大程度上反映了神经源性 以及如何在临床上实施，以改善对SB患者的管理。

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.