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）的诊断由于其症状与其他疾病的症状重叠而变得复杂，尤其是在早期阶段。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。这些因素使得客观生物标志物的发现成为当务之急，但许多挑战阻碍了其发展。尽管一些帕金森病相关蛋白的脑脊液水平在帕金森病患者中发生了改变，但迄今为止没有发现足够特异性的药物来区分帕金森病、早期诊断帕金森病或追踪其进展。分析实验已经鉴定出大量潜在的候选物，但是蛋白质特异性检测的开发通常依赖于可能无法获得的高质量、良好表征的抗体组，这在进一步开发这些候选物时遇到了重大瓶颈。因此，在这项研究中，我们提出了多管齐下的努力，包括各种补充策略，以优化识别 P 生物标志物的可能性。首先，我们将通过确定这些蛋白质或它们的翻译后修饰形式是否在疾病诊断或监测进展中表现良好，进一步探索先前观察到的在PD中脑脊液变化的蛋白质的最大效用。其次，我们将通过使用新开发的基于肽的平台来扩大对脑脊液生物标志物的搜索，这将使我们能够进行高通量靶向发现，然后对人类患者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，以允许对表现进行独立验证和评估，作为所有有希望的候选人的进展标记。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队列的血浆样本中表现最好的候选者的表现，将生物标志物发现过程扩展到更容易收集的样本类型——血浆。最后，我们将在选择的几个队列中测试最佳候选生物标志物，无论是在血浆还是脑脊液中，这些队列包括大量有帕金森病风险的受试者群体，以确定能够在帕金森病最早阶段诊断的生物标志物，此时治疗可能是最有效的。重要的是，这个过程的每一步都为生物标志物研究迈出了新的一步，提供了改进 PD 诊断过程的机会，有助于寻找更好的治疗方法。