Large Scale Biomarker Discovery and Validation for Parkinsons Disease

描述（由申请人提供）：帕金森病（PD）的诊断由于其症状与其他疾病的症状重叠而变得复杂，特别是在早期阶段。此外，由于缺乏对疾病进展的客观评估，PD的临床管理受到阻碍。这些因素使得发现客观生物标志物成为当务之急，但一些挑战阻碍了它们的发展。尽管PD患者的CSF中某些PD相关蛋白的水平发生了变化，但迄今为止发现的这些蛋白都不足以特异性区分帕金森病，在早期诊断PD或追踪其进展。分析实验已经确定了大量的潜在候选物，但是蛋白质特异性测定的开发通常依赖于可能无法获得的高质量、良好表征的抗体集，这在进一步开发这些候选物时存在显著的瓶颈。因此，在这项研究中，我们提出了一个多管齐下的努力，包括各种互补的策略，以优化识别P生物标志物的可能性。首先，我们将进一步探索先前观察到的蛋白质在PD中CSF中变化的最大效用，通过确定这些蛋白质或其经过修饰的形式是否在疾病诊断或监测进展中表现良好。其次，我们将通过使用新开发的基于肽的平台来扩大对CSF生物标志物的搜索，这将使我们能够进行高通量的靶向发现，然后对来自人类患者的样本中的特定肽生物标志物进行基于质谱的测量。值得注意的是，我们将利用多个大型队列的独特组合，包括纵向收集样本的队列，以允许独立验证和评估所有有希望的候选人的进展标志物的性能。此外，我们将开发几种新的生物标志物发现技术，包括基于适体或基于RNA筛选/测序的分析。此外，我们将尝试将生物标志物发现过程扩展到更容易收集的样品类型，血浆，通过检查我们在来自相同队列的血浆样品中表现最好的候选物的性能。最后，我们将在选定的几个队列中检测最佳候选生物标志物（无论是血浆还是CSF），以纳入有PD风险的富集受试者人群，从而确定能够在治疗可能最有效的最早阶段诊断PD的生物标志物。重要的是，这一过程的每一步都为生物标志物研究向前迈出了新的一步，为改善PD诊断过程提供了机会，有助于寻找更好的治疗方法。 公共卫生相关性：有效的生物标志物，无论是在CSF还是血浆中鉴定，都将非常有助于帕金森病的临床诊断，跟踪其进展以及评估治疗效果。

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. PUBLIC HEALTH RELEVANCE: Effective biomarkers, whether identified in CSF or plasma, will be extremely helpful to clinical diagnosis of Parkinson's disease, following its progression a well as assessment of treatment effects.