Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease

约翰霍普金斯大学医学帕金森病生物标志物的发现

• 批准号: 8554394
• 负责人: Ted M. Dawson
• 金额: $ 75.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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/8554394
• 关键词: ABL1 gene; Address; Adverse effects; Autopsy; Biological Assay; Biological Markers; Blood; Brain; Centers of Research Excellence; Cerebrospinal Fluid; Cessation of life; Clinic; Clinical; Clinical Treatment; Cognition; Cognitive; Consensus; Data; Diagnosis; Diagnostic; Digestion; Disease; Disease Marker; Disease Progression; Foxes; Future; Guidelines; Health; Individual; Investigation; Lead; Lewy Bodies; Longitudinal Studies; Mass Spectrum Analysis; Medicine; Methods; Motor; Movement Disorders; Parkinson Disease; Participant; Pathogenesis; Pathologic; Patients; Peptides; Phase II Clinical Trials; Physicians; Post-Translational Protein Processing; Proteins; Proteomics; Recruitment Activity; Research; Research Personnel; Site; Sleep; Smell Perception; Source; Staging; Standardization; Symptoms; System; Testing; Time; Trypsin; Tyrosine; Tyrosine Phosphorylation; alpha synuclein; c-abl Proto-Oncogenes; clinical Diagnosis; cohort; improved; improved functioning; inhibitor/antagonist; mass spectrometer; mortality; multiple reaction monitoring; novel; parkin gene/protein; programs; progression marker; public health relevance; success; synuclein

DESCRIPTION (provided by applicant): We are seeking to improve the diagnosis and treatment of patients with Parkinson disease (PD). Five years of support will allow us to characterize a cohort of patients throughout the PD disease spectrum and matched healthy controls in a systematic and generalizable manner, and then obtain their blood and cerebrospinal fluid (CSF) to identify biomarkers. We will assess whether specific posttranslational modifications to c-Abl, a-synuclein, parkin and parkin substrates (AIMP2, FBP-1 and PARIS) are potential biomarkers. Our clinical and cognitive testing and our biofluid ascertainment methods will follow guidelines from the RFA-NS-1211, the Michael J. Fox Parkinson's Progression Markers Initiative (PPMI), and the consensus opinion of the Udall Centers regarding cognitive testing. The clinical characterization will include extensive motor testing as well as assessments of many of the non-motor facets of PD, including cognition, sleep, and smell. Many of our study participants will have agreed to autopsy through their participation in the Johns Hopkins Medicine Morris K. Udall Center of Parkinson Disease Research of Excellence, allowing for confirmation of their clinical diagnosis and further investigation of the biomarkers that we identify. The blood will be obtained every 6 months at the time of clinical characterization and the CSF will be obtained yearly. Success of the clinical characterization will allow for a cohort of well-characterized individuals with blood and CSF that others and we may correlate with markers in their blood and CSF. Multiple reaction monitoring mass spectrometric assays using a Perfinity workstation inline to a Thermo Vantage triple quadrupole mass spectrometer with on-column trypsin digestion will be used to identify specific posttranslational modifications (PTMs) to proteins integral to PD pathogenesis to differentiate individuals with PD from healthy controls and if these PTMs and proteins integral to PD follow the clinical progression of PD. Success of the biomarker testing will determine if these peptides are diagnostic or progression markers for PD.

描述（由申请人提供）：我们正在寻求改善帕金森病（PD）患者的诊断和治疗。五年的支持将使我们能够以系统且可推广的方式描述整个 PD 疾病谱系的一组患者的特征并匹配健康对照，然后获取他们的血液和脑脊液 (CSF) 以识别生物标志物。我们将评估 c-Abl、a-突触核蛋白、parkin 和 Parkin 底物（AIMP2、FBP-1 和 PARIS）的特定翻译后修饰是否是潜在的生物标志物。我们的临床和认知测试以及生物体液确定方法将遵循 RFA-NS-1211、Michael J. Fox Parkinson's Progression Markers Initiative (PPMI) 的指南以及 Udall 中心关于认知测试的共识意见。临床特征将包括广泛的运动测试以及对帕金森病许多非运动方面的评估，包括认知、睡眠和嗅觉。我们的许多研究参与者都同意通过参与约翰·霍普金斯大学医学莫里斯·尤德尔帕金森病卓越研究中心进行尸检，从而确认他们的临床诊断并进一步研究我们确定的生物标志物。在临床表征时每 6 个月采集一次血液，每年采集一次脑脊液。临床特征的成功将允许获得一组具有良好特征的个体的血液和脑脊液，其他人和我们可以将其与他们的血液和脑脊液中的标记物相关联。使用 Perfinity 工作站与 Thermo Vantage 三重四极杆质谱仪串联并具有柱上胰蛋白酶消化功能的多反应监测质谱分析将用于识别 PD 发病机制中不可或缺的蛋白质的特定翻译后修饰 (PTM)，从而将 PD 个体与健康对照区分开来这些 PTM 和 PD 不可或缺的蛋白质是否遵循 PD 的临床进展。生物标志物测试的成功将决定这些肽是否是帕金森病的诊断或进展标志物。