Establishing clinical utility of CSF biomarkers for PD

建立脑脊液生物标志物对 PD 的临床应用

• 批准号: 8882847
• 负责人: AKHILESH PANDEY
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882847
• 关键词: ABL1 gene; Adopted; Area; Biological Assay; Biological Markers; Brain; Clinical; Clinical Research; Data; Development; Diagnosis; Diagnostic; Disease; Disease Marker; Disease Progression; Event; Foundations; Foxes; Functional disorder; General Population; Goals; Legal patent; Link; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Monitor; National Institute of Neurological Disorders and Stroke; Outcome; Palliative Care; Parkinson Disease; Pathogenesis; Pathologic; Pathway interactions; Patient Care; Patient Monitoring; Patients; Peptides; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Prognostic Marker; Protein Kinase; Protein Tyrosine Kinase; Proteins; Quality of life; Reading; Relative (related person); Research; Research Project Grants; Role; Sampling; Severities; Severity of illness; Signal Transduction; Site; Staging; TNFRSF5 gene; Testing; Therapeutic; Time; Tyrosine; alpha synuclein; base; c-abl Proto-Oncogenes; clinical Diagnosis; cohort; disease diagnosis; improved; multiple reaction monitoring; nervous system disorder; neuron loss; novel; novel diagnostics; novel strategies; parkin gene/protein; patient advocacy group; prognostic; success; synuclein

PROJECT SUMMARY- PROJECT 3: ESTABLISHING CLINICAL UTILITY OF CSF BIOMARKERS FOR PD Accurate diagnosis of Parkinson's disease (PD) and monitoring of PD patients remain challenging and preclude the most effective patient care. Although the NINDS and other PD patient advocacy groups such as the Michael J. Fox Foundation have recognized the need for both diagnostic and prognostic PD biomarkers, no such biomarkers have been validated thus far. This Clinical Research Project will utilize Multiple Reaction Monitoring-Mass Spectrometry (MRM-MS) to determine if specific protein phosphorylation events can be used as novel PD-specific diagnostic/prognostic biomarkers. Previous research has shown that the non-receptor tyrosine kinase, c-Abl, phosphorylates α–Synuclein at the Y-39 site and Parkin at the Y-143 site. During PD, dysregulation of these two pathways ultimately leads to neuronal cell death, which in turn leads to the clinical manifestations of PD. In preliminary studies, we have already developed MRM-MS based quantitative assays to monitor these phosphorylated and unphosphorylated forms of α-Synuclein and Parkin in CSF samples. Our hypothesis is that dysregulation of c- Abl signaling cascade is intrinsically linked to PD pathogenesis and that the relative phosphorylation state of downstream c-Abl substrates, α-Synuclein and Parkin, should provide a sensitive read-out for the presence and/or the severity of PD. Aim 1 will measure the relative concentration of the Y-39 tryptic peptide of α-Synuclein in both its phosphorylated and unphosphorylated forms in the CSF of PD patients and controls. This assay will be employed in several clinical cohorts to determine whether the phosphorylated Y-39 residue can function as (i) a diagnostic marker by differentiating between PD patients and controls and/or (ii) a prognostic PD marker in patients that can be used for assessment of early and late (more severe) stages of PD. Aim 2 will adopt the same approach as described in Aim 1 to test whether c-Abl mediated phosphorylation of Parkin at Y-143 can be used to facilitate either diagnosis with PD or patient monitoring as a function of disease severity. Taken together, this project will identify and validate c-Abl substrates as novel diagnostic/prognostic protein-based biomarkers that have the potential to provide clinicians with novel strategies for establishing a definitive diagnosis of PD and/or for monitoring the severity of disease in patients with PD.

项目总结-项目3：确定用于PD的CSF生物标志物的临床效用 帕金森病（PD）的准确诊断和PD患者的监测仍然具有挑战性， 妨碍了最有效的病人护理虽然NINDS和其他PD患者倡导组织， 迈克尔·J·福克斯基金会已经认识到诊断和预后PD生物标志物的必要性， 这些生物标志物迄今已得到验证。本临床研究项目将利用多重反应 质谱分析（MRM-MS），以确定是否可以使用特定的蛋白磷酸化事件 作为新的PD特异性诊断/预后生物标志物。 先前的研究表明，非受体酪氨酸激酶c-Abl使α-突触核蛋白磷酸化 在Y-39站点和Y-143站点的Parkin。在PD期间，这两种途径的失调最终导致 神经元细胞死亡，这反过来又导致PD的临床表现。在初步研究中， 已经开发了基于MRM-MS的定量分析，以监测这些磷酸化和 CSF样品中α-突触核蛋白和帕金蛋白的非磷酸化形式。我们的假设是c- Abl信号级联与PD发病机制有内在联系， 下游c-Abl底物，α-突触核蛋白和Parkin，应该提供一个灵敏的读数， 和/或PD的严重程度。 目的1测定α-突触核蛋白Y-39胰蛋白酶肽在两种组织中的相对浓度， 在PD患者和对照的CSF中磷酸化和非磷酸化的形式。本试验将 在几个临床队列中使用，以确定磷酸化的Y-39残基是否可以起到（i） 通过区分PD患者和对照的诊断标志物，和/或（ii）PD患者中的预后PD标志物， 可用于评估早期和晚期（更严重）PD的患者。 目的2将采用与目的1所述相同的方法来测试c-Abl介导的磷酸化是否 在Y-143的Parkin的可用于促进PD诊断或患者监测， 疾病严重程度。 总之，该项目将确定和验证c-Abl底物作为新的诊断/预后 基于蛋白质的生物标志物，有可能为临床医生提供新的策略， PD的明确诊断和/或监测PD患者的疾病严重程度。