Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease

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疾病谱系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。我们将评估对c-Abl、a-synuclein、parkin和parkin底物（AIMP2、FBP-1和PARIS）的特定翻译后修饰是否为潜在的生物标志物。我们的临床和认知测试以及我们的生物体液测定方法将遵循RFA-NS-1211、Michael J. Fox帕金森病进展标志物倡议（PPMI）和Udall中心关于认知测试的共识意见的指导方针。临床特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.尤德尔帕金森病卓越研究中心的参与进行尸检，从而确认他们的临床诊断并进一步调查我们确定的生物标志物。临床鉴定时每6个月取一次血，每年取一次脑脊液。临床特征的成功将允许一个具有血液和脑脊液特征的个体队列，其他人和我们可能与他们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（柱上胰蛋白酶消化）连接的多重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（PTMs），以区分PD个体与健康对照，以及这些PTMs和PD不可或缺的蛋白质是否跟随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PD的诊断或进展标志物。

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.