BIOMARKER DISCOVERY AND VALIDATION IN PSP

PSP 中生物标志物的发现和验证

• 批准号: 9750090
• 负责人: Ted M. Dawson
• 金额: $ 94.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750090
• 关键词: Affect; Algorithms; Area; Basal Ganglia; Biochemical Process; Bioinformatics; Biological; Biological Assay; Biological Markers; Blinded; Brain; Brain region; Cell Death; Cells; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clinical; Clinical Trials; Collection; Complex; Data; Data Discovery; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Enrollment; Ensure; Evaluation; Exhibits; Fourier Transform; Functional disorder; Globus Pallidus; Goals; Impairment; Individual; Label; Longevity; Mass Spectrum Analysis; Mediating; Medical History; Metabolic; Methods; Monitor; Motor; Neurodegenerative Disorders; Neurons; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathologic; Pathway interactions; Patients; Pennsylvania; Peptides; Performance; Pharmacotherapy; Progressive Supranuclear Palsy; Proteins; Proteome; Proteomics; Quality of life; Reaction; Reproducibility; Resolution; Resources; Sampling; Set protein; Techniques; Technology; Testing; Time Management; Universities; Validation; base; biomarker discovery; biomarker validation; brain tissue; candidate marker; candidate validation; clinical practice; cohort; cost; daily functioning; diagnostic biomarker; differential expression; disorder control; experimental study; nervous system disorder; neuroimaging; outcome forecast; patient response; programs; prospective; protein aggregation; protein biomarkers; proteomic signature; tau Proteins; validation studies

ABSTRACT Progressive supranuclear palsy (PSP) is a devastating atypical parkinsonian disorder that currently lacks meaningful symptomatic therapies, reduces lifespan and greatly impairs daily function and quality of life. It is often difficult to distinguish from Parkinson disease (PD) clinically, which is crucial for appropriate and timely management, prognosis and clinical trial enrollment. Despite a critical need for a reliable diagnostic marker for parkinsonian disorders, there is currently no biomarker that can be used in routine clinical practice to distinguish between PSP and PD. The purpose of this project is to discover cerebrospinal fluid (CSF) biomarkers that reliably distinguish between PSP, PD and healthy individuals. The difficulty of identifying reliable biomarkers can be attributed to the variability of clinical samples, low abundance of proteins that are involved in the pathogenesis of PSP and PD, and the lack of reproducibility in validating biomarker candidates. To overcome these limitations, we propose use of a large CSF cohort with greater statistical power for true discovery, and deep proteome analysis to reveal PSP biomarkers that are involved in PSP pathogenesis, but are present at low abundance. In addition, multiplexed sample analysis by isobaric tandem mass tagging (TMT) with a common reference for data normalization will ensure robust analytical precision of quantitative proteomic data for discovery from a larger set of samples. Moreover, additional proteomic analysis of brain tissue will be used to select those biomarkers that show differential expression in CSF as well as the globus pallidus, a representative brain region used to pathologically define PSP. These discovery platforms will utilize a bioinformatics approach to select the most plausible candidates for targeted validation studies followed by an intensive validation of the discovered biomarker candidates. To achieve these goals, we propose four aims: Specific Aim 1: To prospectively collect CSF on patients with clinically well-characterized PSP. Specific Aim 2: To discover proteins that are differentially expressed in patients with PSP compared to controls and PD. We plan to carry out a quantitative proteomic analysis of CSF and globus pallidus samples from patients with PSP, PD and from controls by employing TMT-based multiplexing technology. With this approach, we expect to obtain a more comprehensive coverage of a larger number of proteins quantified across the analyzed samples. Specific Aim 3: To prioritize PSP biomarker candidates based on an integrative analysis of alterations in CSF and globus pallidus. By integrating the expression changes in CSF and brain tissue with a network approach that takes advantage of the known biological pathways that have been described in PSP, our proposal will be able to select reliable PSP biomarker candidates for validation by targeted PRM experiments. Specific Aim 4: To validate candidate protein biomarkers in a larger cohort using targeted parallel reaction monitoring (PRM) mass spectrometry using CSF samples from a PSP cohort at Johns Hopkins University, the University of Pennsylvania, UCSF and PDBP. Biomarkers that are selected by algorithms based on these PRM experiments will finally be confirmed using blinded PDBP CSF samples from PSP and will be compared to CSF samples from PD. Through the approaches outlined above, we expect to discover and validate reliable PSP biomarkers that are distinguishable from PD in a reproducible manner.

抽象的 进行性核上麻痹（PSP）是一种毁灭性的非典型帕金森病，目前缺乏 有意义的症状疗法，降低寿命并大大损害日常功能和生活质量。这是 在临床上通常很难与帕金森氏病（PD）区分开，这对于适当和及时至关重要 管理，预后和临床试验入学率。尽管至少需要可靠的诊断标记 帕金森氏症疾病，目前没有生物标志物可以在常规临床实践中使用 区分PSP和PD。该项目的目的是发现脑脊液（CSF） 可靠地区分PSP，PD和健康个体的生物标志物。识别的困难 可靠的生物标志物可以归因于临床样本的变异性，蛋白质的丰度低 参与PSP和PD的发病机理，以及在验证生物标志物候选物方面缺乏可重复性。 为了克服这些限制，我们建议使用具有更大统计能力的大型CSF队列 发现和深度蛋白质组分析以揭示与PSP发病机理有关的PSP生物标志物，但 以低丰度存在。此外，通过等速串联质量标记多路复用样品分析 （TMT）具有用于数据归一化的常见参考，将确保定量的鲁棒分析精度 从较大样品集中发现的蛋白质组学数据。此外，大脑的其他蛋白质组学分析 组织将用于选择那些在CSF和Globus中显示差异表达的生物标志物 Pallidus，一种代表性的大脑区域，用于病理定义PSP。这些发现平台将使用 一种生物信息学方法，以选择针对目标验证研究的最合理的候选者，然后 对发现的生物标志物候选者的密集验证。为了实现这些目标，我们提出了四个目标： 具体目标1：前瞻性地收集临床表征良好的PSP患者的CSF。具体目标 2：发现与对照组和PD相比，发现在PSP患者中差异表达的蛋白质。我们 计划对PSP患者的CSF和Globus Pallidus样品进行定量蛋白质组学分析， 通过采用基于TMT的多路复用技术，PD和控制。通过这种方法，我们希望 获取对分析样品中量化的大量蛋白质的更全面覆盖范围。 特定目的3：基于CSF改变的综合分析，优先考虑PSP生物标志物候选者 和Globus Pallidus。通过通过网络方法整合CSF和脑组织中的表达变化 利用PSP中描述的已知生物途径的优势，我们的建议将是 能够通过目标PRM实验选择可靠的PSP生物标志物候选物进行验证。具体目标4： 使用靶向平行反应监测（PRM）在较大队列中验证候选蛋白生物标志物 使用来自约翰·霍普金斯大学PSP队列的CSF样品的质谱法，大学 宾夕法尼亚州，UCSF和PDBP。基于这些PRM实验的算法选择的生物标志物 最终将使用PSP的盲PDBP CSF样品确认，并将与CSF样品进行比较 来自PD。通过上面概述的方法，我们希望发现并验证可靠的PSP生物标志物 可以以可重复的方式与PD区分开。