Large Scale Biomarker Discovery and Validation for Parkinsons Disease

帕金森病的大规模生物标志物发现和验证

• 批准号: 8554930
• 负责人: Jing Zhang
• 金额: $ 109.21万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554930
• 关键词: Address; Antibodies; Applications Grants; Biological; Biological Assay; Biological Markers; Blood; Brain; Cerebrospinal Fluid; Clinical; Clinical Data; Clinical Management; Collection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early identification; Funding; Future; Goals; Human; Impaired cognition; Investigation; Mass Spectrum Analysis; Measurement; Methods; Monitor; Motor Manifestations; Nerve Degeneration; Neurons; Outcome; Parkinson Disease; Parkinsonian Disorders; Patients; Peptides; Performance; Peripheral; Phase II Clinical Trials; Plasma; Population; Post-Translational Protein Processing; Process; Protein Isoforms; Proteins; RNA; Research; Risk; Sampling; Secondary Parkinson Disease; Sensitivity and Specificity; Serum; Source; Specimen; Staging; Symptoms; Syndrome; Techniques; Testing; Therapeutic; Validation; Work; aptamer; base; candidate marker; clinical Diagnosis; cohort; disease diagnosis; disorder control; high risk; improved; motor impairment; new technology; novel; pre-clinical; prognostic; progression marker; public health relevance; research study; screening; success; synuclein; tool; treatment effect

DESCRIPTION (provided by applicant): Diagnosis of Parkinson's disease (PD) is complicated by the overlap of its symptoms with those of other disorders, especially at early stages. Additionally, clinical management of PD is hampered by a lack of objective assessment of disease progression. These factors make discovery of objective biomarkers an urgent priority, but a number of challenges have impeded their development. Although CSF levels of some PD-related proteins are altered in PD patients, none discovered so far are specific enough to differentiate between parkinsonian disorders, diagnose PD at early stages, or trace its progression. Profiling experiments have identified large numbers of potential candidates, but the development of protein-specific assays, which often depend on high-quality, well-characterized antibody sets that may not be available, presents a significant bottleneck in carrying these candidates through further development. Therefore, in this study, we propose a multi-pronged effort including a variety of complementary strategies to optimize the possibility of identifying P biomarkers. First, we will further explore the maximal utility of proteins previously observed to change in CSF in PD, by determining whether these proteins, or with post-translationally modified forms of them, perform well in disease diagnosis or monitoring progression. Second, we will expand the search for CSF biomarkers by using a newly developed peptide-based platform, which will allow us to perform high-throughput targeted discovery, followed by mass spectrometry-based measurement of specific peptide biomarkers in samples from human patients. Notably, we will make use of a unique combination of multiple large cohorts, including one in which samples are collected longitudinally, to allow independent validation and assessment of performance as progression markers of all promising candidates. Additionally, we will develop several novel techniques for biomarker discovery, including profiling based on aptamers, or based on RNA screening/sequencing. Further, we will attempt to extend the biomarker discovery process to a more easily collected sample type, plasma, by examining the performance of our best-performing candidates in plasma samples from the same cohorts. Finally, we will test the best candidate biomarkers, whether in plasma or CSF, in several cohorts selected to include an enriched population of subjects at risk for PD, in order to identify biomarkers capable of diagnosing PD at its earliest stages, when treatment is likely most effective. Importantly, each step of this process provides a novel step forward in biomarker research, providing the opportunity to improve the PD diagnostic process facilitate the search for better treatments.

描述（由申请人提供）：帕金森氏病（PD）的诊断因其与其他疾病的症状重叠而复杂化，尤其是在早期阶段。此外，缺乏对疾病进展的客观评估，可以阻碍PD的临床管理。这些因素使发现客观生物标志物成为紧迫的优先事项，但是许多挑战阻碍了他们的发展。尽管PD患者的某些PD相关蛋白的CSF水平发生了变化，但到目前为止，没有人发现足以区分帕金森氏症，在早期阶段诊断PD或追踪其进展。分析实验已经确定了大量潜在的候选物，但是蛋白质特异性测定的开发通常取决于可能无法使用的高质量，良好的抗体集，在通过进一步开发中携带这些候选者时具有重要的瓶颈。因此，在这项研究中，我们提出了一项多管齐下的努力，包括各种补充策略，以优化鉴定P生物标志物的可能性。首先，我们将进一步探讨以前观察到的蛋白质的最大效用，通过确定这些蛋白质是在PD中改变CSF的最大效用，是在疾病诊断或监测进展方面表现良好的蛋白质，或者使用后翻译后修饰的形式效果很好。其次，我们将通过使用新开发的基于肽的平台来扩展对CSF生物标志物的搜索，这将使我们能够执行高通量的目标发现，然后在人类患者的样品中基于质谱测量对特定肽生物标志物的测量。值得注意的是，我们将利用多个大型同类人群的独特组合，包括纵向收集样品的组合，以允许对绩效的独立验证和评估作为所有有前途的候选人的进步标记。此外，我们将开发几种用于生物标志物发现的新技术，包括基于适体或基于RNA筛选/测序的分析。此外，我们将尝试通过检查来自同一同龄人的等离子体样本中表现最好的候选者的性能，将生物标志物发现过程扩展到更容易收集的样本类型。最后，我们将测试最佳的候选生物标志物，无论是在血浆中还是CSF中，在几个人群中都选择包括PD风险的丰富受试者人群，以识别能够在治疗最有效的情况下能够在最早诊断PD的生物标志物。重要的是，此过程的每个步骤都为生物标志物研究提供了新的一步，这为改善PD诊断过程提供了机会，可以促进寻找更好的治疗方法。