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: 8472291
• 负责人: Ted M. Dawson
• 金额: $ 60.98万
• 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/8472291
• 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; 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. PUBLIC HEALTH RELEVANCE: Parkinson disease is a clinical diagnosis and treatments do not change disease progression and are associated with unacceptable side effects. There are currently no diagnostic markers of disease or markers of progression of Parkinson disease. By identifying diagnostic or progression markers for PD we will have the potential to improve the function, health, and mortality of individuals with 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和可推广的方式描述整个PD疾病谱的患者队列和匹配的健康对照，然后获得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（AIMP 2、FBP-1和巴黎）的特异性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我们的生物流体确定方法将遵循RFA-NS-1211，Michael J. Fox帕金森氏病进展标志物倡议（PPMI）以及Udall中心关于认知测试的共识。临床表征将包括广泛的运动测试以及PD的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将同意通过他们在约翰霍普金斯医学莫里斯K. Udall帕金森病卓越研究中心，允许确认他们的临床诊断和进一步调查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CSF。临床表征的成功将允许具有血液和CSF的良好表征的个体的队列，其他人和我们可能与其血液和CSF中的标志物相关。将使用Percoln工作站与Thermo Vantage三重四极杆质谱仪（采用柱上胰蛋白酶消化）串联进行多反应监测质谱测定，以鉴定PD发病机制所必需蛋白质的特异性翻译后修饰（PTM），以区分PD个体与健康对照，以及这些PTM和PD所必需蛋白质是否遵循PD的临床进展。生物标志物测试的成功将确定这些肽是否是PD的诊断或进展标志物。 公共卫生关系：帕金森病是一种临床诊断和治疗不改变疾病进展，并与不可接受的副作用。目前还没有帕金森病的诊断标志物或进展标志物。通过确定PD的诊断或进展标志物，我们将有可能改善PD患者的功能，健康和死亡率。