Discovery, Validation and Clinical Application of Novel, Non-Invasive Biomarkers

描述（由申请人提供）：UCPPS的特发性促使人们深入研究该综合征的诊断和预后临床生物标志物。UCPPS临床相关生物标志物的开发对于有效的临床管理和对UCPPS病理的理解以及推进当前治疗和开发新疗法的目标至关重要。在MAPP-I期间，我们利用我们的交互式Trans-MAPP网络的力量，使用两种不同的方法成功鉴定了一组UCPPS的生物相关的非侵入性尿液生物标志物：（1）基于这种疾病的基本生物学和生理学的生物驱动的生物标志物发现策略和（2）全球蛋白质组学生物标志物发现策略。作为MAPP生物标志物工作组的成员，我们利用我们自己在人类样本库开发和生物采样方面的丰富经验，沿着我们的同事，开发了目前用于获取、运输和储存的“最佳实践”协议。 MAPP网络中的所有人类样本通过我们的定向、生物学驱动的研究，我们分析了MAPP-I期间提供的约500份（迄今为止）尿液样本，以确定如上所述鉴定的六种不同蛋白质生物标志物的存在和量。除了这些单个蛋白质生物标志物的鉴定和验证之外，我们还发现（1）与健康和阳性对照相比，UCPPS显著改变了尿蛋白质组，（2）UCPPS可能以可定义的生物相关模式改变细胞外基质蛋白的调节。我们现在正在完成对我们全球蛋白质组学工作中确定的尿蛋白的验证研究，并打算将它们与我们通过生物驱动的发现研究发现的蛋白质进行多重研究。然后，我们将联合收割机将我们最终验证的生物标志物组与来自其他参与MAPP发现地点的生物和临床数据相结合。多路复用这些标志物将增加任何单独的标志物的预测能力。然后，我们将测试这组生物标志物的能力，以确定UCPPS的存在，监测对治疗的反应，预测疾病进展和发作，并确认改善和解决，有或没有干预。最后，我们将询问这些经验证的诊断靶点告诉我们这些不同UCPPS疾病阶段的机制。这些目标将在以下具体目标范围内实现：目的1评估I期研究中鉴定和验证的尿液生物标志物在UCPPS临床管理中的效用目的2评估我们研究中验证的所有生物标志物与其他trans-MAPP组鉴定和验证的生物和临床数据的多重临床效用目的3阐明机制疾病存在、疾病发作、对干预的反应和消退的基础

DESCRIPTION (provided by applicant): The idiopathic nature of UCPPS has prompted an intense search for diagnostic and prognostic clinical biomarkers of this syndrome. The development of clinically relevant biomarkers of UCPPS is critical to effective clinical management and to the understanding of UCPPS pathology, and to the goal of advancing current treatment and developing novel therapies. During MAPP-I, we have taken advantage of the power of our interactive Trans-MAPP Network to successfully identify a panel of biologically-relevant, noninvasive urinary biomarkers of UCPPS using two distinct approaches: (1) a biologically-driven biomarker discovery strategy grounded in the basic biology and physiology of this disease and (2) a global proteomics biomarker discovery strategy. As members of the MAPP Biomarker Working Group, we exploited our own extensive experience in human sample repository development and biosampling, along with that of our colleagues, to develop the 'Best Practices' protocols that are currently being utilized for the acquisition, shipping and storage of all human samples in the MAPP network. Through our directed, biologically-driven studies, we have analyzed ~500 (to date) urine samples provided during MAPP-I for the presence and amounts of six different protein biomarkers identified as described above. In addition to the identification and validation of these individual protein biomarkers, we also found that (1) UCPPS significantly changes the urinary proteome as compared to that of healthy and positive controls and (2) UCPPS may alter the regulation of extracellular matrix proteins in a definable, biologically-relevant pattern. We are now in the process of completing the validation studies of those urinary proteins identified in our global proteomics work and intend to multiplex them with those discovered through our biologically-driven discovery studies. We will then combine our final validated panel of biomarkers with biologic and clinical data from other participating MAPP discovery sites. Multiplexing these markers will increase the predictive power of any of the markers alone. We will then test the ability of this panel of biomarkers to identify the presence o UCPPS, monitor response to therapy, predict disease progression and episodic flares, and confirm improvement and resolution, with or without intervention. Finally, we will ask what these validated diagnostic targets teach us about mechanism(s) underlying these different UCPPS disease stages. These goals will be met within the context of the following Specific Aims: Aim 1 To assess the utility of the identified and validated urinary biomarkers from Phase I in the clinical management of UCPPS Aim 2 To assess the clinical utility of multiplexing all biomarkers validated in our studies with biologic and clinical data identified and validated by other Trans-MAPP groups Aim 3 To elucidate the mechanism(s) underlying the presence of disease, disease flare, response to intervention and resolution