Peptide Biomarkers for Parkinson Disease

帕金森病的肽生物标志物

• 批准号: 9191379
• 负责人: Jing Zhang
• 金额: $ 53.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191379
• 关键词: Address; Affect; Alzheimer' s Disease; American; Anosmia; Antibodies; Biological Assay; Biological Markers; Blood; Body Fluids; Caring; Cells; Cerebrospinal Fluid; Clinical; Collaborations; Cross-Sectional Studies; Data; Detection; Development; Diagnosis; Differential Diagnosis; Disease; Disease Progression; Early Diagnosis; Elderly; Family; Goals; Human; Image; LRRK2 gene; Longitudinal cohort; Mass Spectrum Analysis; Medical; Monitor; Multiple System Atrophy; Mutation; Neural Cell Adhesion Molecule L1; Neuraxis; Neurodegenerative Disorders; Organ; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Patient Recruitments; Patients; Pennsylvania; Peptides; Performance; Persons; Pharmaceutical Preparations; Pilot Projects; Plasma; Population; Process; Progressive Supranuclear Palsy; Proteins; Proteomics; Quality of life; Reaction; Reproducibility; Research; Research Design; Resources; Risk; Sampling; Sensitivity and Specificity; Severity of illness; Societies; Symptoms; Techniques; Testing; Tocopherols; Transportation; Universities; Validation; Variant; Washington; Work; accurate diagnosis; alpha synuclein; base; biomarker discovery; biomarker identification; biomarker panel; blood-based biomarker; body system; cohort; cost; deprenyl; design; diagnostic biomarker; disease diagnosis; disorder control; exosome; hyposmia; improved; microvesicles; parkin gene/protein; pre-clinical; progression marker; public health relevance; tau Proteins; treatment effect

 DESCRIPTION (provided by applicant): Objective, reliable, and reproducible biomarkers are clearly needed to assist with accurate diagnosis of Parkinson disease (PD), especially at early stages, as well as for facilitating differential diagnosis and disease monitoring. The proposal is designed to meet several major challenges of current biomarker research, specifically: 1) significant variations associated with antibody-based protein assays, 2) low sensitivity and specificity of blood based markers, and 3) detection of PD at early stages. To address the problems of antibody-based assays, our strategy is development of targeted mass spectrometry-based techniques, such as selected reaction monitoring (SRM), to identify unique peptide markers derived from proteins either showing promise in previous proteomics profiling, or known to be critical to PD pathogenesis, e.g., α-synuclein, parkin and LRRK2, in human cerebrospinal fluid (CSF). To facilitate discovery and validation of blood based biomarkers, a specific population of central nervous system derived plasma exosomes, the cargo-carrying microvesicles recognized recently to transport biomolecules among different cells or organ systems, will be isolated before SRM analysis. The unique peptide markers will be tested in several large, well-established cohorts, e.g., Udall Centers affiliated with the University of Washington and University of Pennsylvania, DATATOP (Deprenyl and tocopherol antioxidative therapy of parkinsonism) and PPMI (Parkinson Progression Marker Initiative), with cross-sectional and longitudinal samples collected, along with extensive clinical characterization. Finally, to improve early diagnosis, we will make use of two cohorts consisting of subjects at elevated risk for PD (i.e., asymptomatic subjects with LRRK2 mutations or anosmia/hyposmia), with the goal of discovering biomarkers capable of identifying subjects with early or premotor PD. The studies designed for this project, if successful, have the potential to result in a panel(s of biomarkers that are robust, with less variation than can currently be achieved, and in a body fluid that is readily accessible in a regular clinical setting. Markers for early diagnosis and progression of PD are critical in understanding how to arrest or slow PD progression.

 描述（由申请人提供）：显然需要客观、可靠和可重复的生物标志物来协助帕金森病（PD）的准确诊断，特别是在早期阶段，以及促进鉴别诊断和疾病监测。满足当前生物标志物研究的几个主要挑战，特别是：1）与基于抗体的蛋白质测定相关的显着变化，2）基于血液的标志物的低敏感性和特异性，以及3）早期检测PD以解决抗体的问题。 -基于分析中，我们的策略是开发基于靶向质谱的技术，例如选择反应监测 (SRM)，以识别源自蛋白质的独特肽标记，这些标记在之前的蛋白质组学分析中显示出前景，或者已知对 PD 发病机制至关重要，例如，人脑脊液 (CSF) 中的 α-突触核蛋白、parkin 和 LRRK2 为了促进基于血液的生物标志物（中枢神经系统来源的血浆外泌体的特定群体）的发现和验证。最近被认为可以在不同细胞或器官系统之间运输生物分子的载货微泡将在 SRM 分析之前被分离出来，这些独特的肽标记将在几个大型、成熟的队列中进行测试，例如华盛顿大学附属的 Udall 中心和宾夕法尼亚大学，DATATOP（Deprenyl 和生育酚抗帕金森病抗氧化疗法）和 PPMI（帕金森进展标记计划），具有横截面和纵向最后，为了改善早期诊断，我们将利用两个由 PD 风险较高的受试者（即具有 LRRK2 突变或嗅觉丧失/嗅觉减退的无症状受试者）组成的队列。能够识别患有早期或运动前帕金森症的受试者的生物标志物如果成功的话，有可能产生一组稳健的生物标志物，其变化比目前的要少。实现了这一点，并且在常规临床环境中易于获得的体液中，用于早期诊断和进展的帕金森病标志物对于了解如何阻止或减缓帕金森病的进展至关重要。