Project 3: Plasma Biomarkers for Parkinsonism in Welders

环境中接触金属，包括锰，是焊接或相关行业工人患帕金森症(PS)的重要危险因素。然而，金属介导的PS与特发性帕金森病(IPD)的相关性仍有待研究。临床上，金属相关性PS和IPD之间的鉴别诊断是困难的，即使是最好的医生也是如此。这项建议的重点是发现焊工特有的血浆生化标志物，用于各种PS的鉴别诊断，监测PS的进展，并识别有可能发展为致残PS的人群。要使用的技术包括 最先进的蛋白质组学，目前在我们实验室积极应用于揭示人脑组织和脑脊液(CSF)中IPD的特定生物标记物。目前的建议有三个具体目标：1)使用在IPD患者中发现的脑/脑脊液特异性标记物来区分焊工和IPD患者的血浆样本中的PS；2)使用靶向和无偏倚的定量蛋白质组学来开发焊工PS进展以及焊工早期阶段特有的血浆生物标记物；以及3)确认和验证焊工的PS血浆生物标记物，这是发现生物标记物的关键过程。 这项研究的意义包括：1)查明PS特有的标志物，无论是有症状的焊工还是有患PS风险的人，都将有助于诊断和监测这些患者，并使之能够将有风险的对象从环境中移除，从而防止他们患PS；2)确认金属暴露引起的PS特有的蛋白质标志物可能为该病的发病机制和治疗靶点提出新的建议；以及3)PS标志物如果确定，将可广泛应用，因为即使在发展中国家或发达国家的偏远地区，也可以在临床环境中轻松实施血浆检测。

Environmental exposure to metals, including manganese, is an important risk factor for the development of parkinsonism (PS) in workers of welding or related industries. However, the relevance of metal-mediated PS to idiopathic Parkinson's disease (iPD) remains to be characterized. Clinically, differential diagnosis between metal-related PS and iPD is difficult, even in the best hands. This proposal is focused on discovering plasma biochemical markers unique to welders for differential diagnosis of various PS, monitoring PS progression, and identification of the population at risk for developing disabling PS. The techniques to be utilized are state-of-the-art proteomics that are actively employed currently in our laboratory in revealing biomarkers specific to iPD in both human brain tissue and cerebrospinal fluid (CSF). Three specific aims are designed for the current proposal: 1) to differentiate PS in the plasma samples of welders from those of iPD using brain/CSF specific markers identified in iPD patients, 2) to develop plasma biomarkers unique to PS progression as well as early stages in welders using targeted and nonbiased quantitative proteomics, and 3) to confirm and validate PS plasma biomarkers in welders, which is a key process of biomarker discovery. The significance of this investigation includes: 1) identification of markers unique to PS, both in symptomatic welders and those at risk for developing PS, will help diagnose and monitor these patients as well as make it possible to remove the subjects at risk from the environment, thereby preventing them from developing PS; 2) identification of protein markers unique to PS secondary to metal exposure likely suggests novel pathogenesis and therapeutic targets for the disease process; and 3) PS markers, if identified, can be widely utilized, given that plasma-based assays can be readily implemented in a clinical setting, even in developing countries or in remote areas of developed countries.