Large Scale Biomarker Discovery and Validation for Parkinsons Disease

描述(申请人提供)：帕金森氏病(PD)的诊断复杂，其症状与其他疾病的症状重叠，特别是在早期阶段。此外，由于缺乏对疾病进展的客观评估，帕金森病的临床治疗受到阻碍。这些因素使得发现客观生物标记物成为当务之急，但一些挑战阻碍了它们的发展。尽管帕金森病患者脑脊液中一些PD相关蛋白的水平发生了改变，但到目前为止还没有发现有足够的特异性来区分帕金森病、早期诊断PD或追踪其进展。图谱实验已经确定了大量潜在的候选抗体，但蛋白质特异性分析的发展往往依赖于可能无法获得的高质量、特征良好的抗体集，这是使这些候选抗体进一步发展的一个重大瓶颈。因此，在这项研究中，我们提出了一种多管齐下的努力，包括各种补充策略，以优化识别P生物标记物的可能性。首先，我们将进一步探索先前观察到的在帕金森病脑脊液中变化的蛋白质的最大效用，通过确定这些蛋白质或它们的翻译后修饰形式在疾病诊断或监测进展中是否表现良好。其次，我们将通过使用新开发的基于多肽的平台来扩大对脑脊液生物标记物的搜索，这将使我们能够进行高通量的靶向发现，然后基于质谱学对人类患者样本中的特定多肽生物标记物进行测量。值得注意的是，我们将利用多个大样本的独特组合，包括纵向收集样本的组合，以允许独立验证和评估作为所有有希望的候选人的进步标记的表现。此外，我们将开发几种新的生物标记物发现技术，包括基于适体的图谱分析，或基于RNA筛选/测序。此外，我们将尝试将生物标记物的发现过程扩展到更容易收集的样本类型-血浆，通过检查我们在相同队列中的血浆样本中表现最好的候选样本的表现。最后，我们将在几个队列中测试最佳候选生物标记物，无论是在血浆还是脑脊液中，选择包括帕金森病风险人群的丰富人群，以便识别能够在治疗可能最有效的早期阶段诊断帕金森病的生物标记物。重要的是，这一过程的每一步都提供了生物标记物研究的新进展，为改进PD诊断过程提供了机会，促进了寻找更好的治疗方法。

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.