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

新型非侵入性生物标志物的发现、验证和临床应用

• 批准号: 9312807
• 负责人: Richard Sang-yong Lee
• 金额: $ 23.33万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312807
• 关键词: Affect; Basic Science; Biochemistry; Biological; Biological Markers; Biology; Boston; Clinical; Clinical Data; Clinical Management; Clinical Sciences; Cohort Studies; Data; Development; Diagnostic; Diagnostic tests; Disease; Disease Progression; Enzyme Inhibitor Drugs; Epidemiology; Extracellular Matrix Proteins; Face; Family; Flare; Foundations; Funding; Goals; Human; Individual; Intervention; Investigation; Location; Longitudinal Studies; Matrix Metalloproteinases; Measures; Monitor; Nature; Pain; Pathology; Patients; Pattern; Pediatric Hospitals; Phase; Phenotype; Physiology; Process; Prophylactic treatment; Prospective cohort study; Proteins; Proteome; Proteomics; Protocols documentation; Regulation; Reporting; Research; Resolution; Risk; Sampling; Severities; Shipping; Site; Subgroup; Symptoms; Syndrome; Testing; Tissue Inhibitor of Metalloproteinases; Treatment Efficacy; Urine; Validation; Work; biomarker discovery; biomarker panel; biomarker-driven; clinical application; clinical biomarkers; clinical development; clinically relevant; cohort; disease phenotype; enzyme activity; experience; human disease; improved; insight; medical schools; member; novel; novel therapeutics; phase 1 study; prognostic; prognostic assays; programs; protein biomarkers; public health relevance; repository; response; success; urinary; validation studies; working group

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

描述(由申请人提供)：UCPPS的特发性促使人们对该综合征的诊断和预后临床生物标志物进行了密集的研究。UCPPS的临床相关生物标志物的开发对于有效的临床治疗和了解UCPPS的病理，以及推进当前治疗和开发新的治疗方法是至关重要的。在MAPP-I期间，我们利用我们的互动Trans-Mapp网络的力量，使用两种不同的方法成功地识别了一组与生物相关的、非侵入性的UCPPS尿液生物标记物：(1)基于这种疾病的基本生物学和生理学的生物驱动型生物标记物发现策略；(2)全球蛋白质组学生物标记物发现策略。作为Mapp Biomarker工作组的成员，我们利用自己在人类样本库开发和生物采样方面的丰富经验，以及我们的同事们的经验，制定了目前用于获取、运输和存储 Mapp网络中的所有人类样本。通过我们定向的、生物驱动的研究，我们已经分析了在MAPP-I期间提供的约500个尿样，以确定上述六种不同蛋白质生物标志物的存在和数量。除了识别和验证这些单独的蛋白质生物标志物外，我们还发现(1)与健康和阳性对照组相比，UCPPS显著改变了尿蛋白质组；(2)UCPPS可能会以一种可确定的、与生物相关的模式改变细胞外基质蛋白的调节。我们目前正在完成对我们全球蛋白质组学工作中发现的那些尿蛋白的验证研究，并打算将它们与通过我们的生物驱动的发现研究发现的那些蛋白进行复合。然后，我们将把我们最终验证的生物标记物小组与来自其他参与MAPP发现站点的生物和临床数据结合起来。多路传输这些标记将单独增加任何标记的预测能力。然后，我们将测试这组生物标志物的能力，以识别UCPPS的存在，监测治疗反应，预测疾病进展和发作性红斑，并确认改善和解决，无论是否干预。最后，我们将询问这些经过验证的诊断指标对这些不同UCPPS疾病阶段背后的机制(S)有何启示。这些目标将在以下特定目标的背景下实现：目标1评估第一阶段中已识别和验证的尿液生物标记物在UCPPS临床管理中的作用2评估将我们研究中验证的所有生物标志物与其他Trans-Mapp小组识别和验证的生物和临床数据相结合的临床实用价值目标3阐明疾病存在、疾病爆发、对干预的反应和解决的机制(S)