PROJECT 3: METABOLOMIC BIOMARKERS OF PARKINSON'S DISEASE

该项目的长期目标是利用临床代谢组学来了解环境 帕金森病的贡献，并制定新的干预策略，以减少风险和管理 结果。PD是一种影响老年人的衰弱性疾病，由于年龄的增长， 美国人口。PD似乎有多种原因与环境暴露，如 农药，尤其是农药。这些药物诱导氧化应激并抑制线粒体 呼吸复合物I，从而促成与PD风险相关的两个生化过程。我们有 组建了一个分析生物化学、神经退行性疾病和生物信息学方面的专家小组， 使用一种新的高通量代谢分析方法，结合生物信息学， 农药暴露和PD发展的特征。这种强大的方法论与 精确分析测定农药含量和氧化应激的能力， 特征可以提供暴露与疾病症状之间的直接联系。查明这类 代谢特征可以在提供早期检测风险的手段方面具有相当大的影响， 提示了用于干预以预防或控制疾病进展的新靶点。代谢组学 该平台允许在10分钟的人血浆分析中检测2000个代谢特征。具体目标 使用该测定来1）描绘血浆、脑脊液和黑质中的代谢变化 在PD小鼠模型中，化学物质（MPTP，狄氏剂）被用于在野生型小鼠中引起症状， 具有降低的适当储存多巴胺的能力的敏感小鼠系（VMAT 2缺陷型），以及具有抗性的 线粒体硫氧还蛋白-2含量增加的小鼠系; 2）确定相关的代谢特征 与PD以及PD和非PD对照中的农药水平;以及3）制定标准化程序， 允许创建人体代谢组学数据的累积数据库。成功完成这些 aims将提供关于暴露于环境化学品的假设的关键新信息， 创建PD风险的代谢平台，可通过临床代谢组学进行评估并作为基础 用于早期干预以预防疾病和治疗方法以延迟进展。

The long-term objectives of this project are to use clinical metabolomics to understand environmental contributions to Parkinson's Disease and develop novel interventional strategies to reduce risk and manage outcome. PD is a debilitating disease affecting elderly which is of growing concern because of the aging of the American population. PD appears to have multiple causes with environmental exposures, such as pesticides, being of particular concern. These agents induce oxidative stress and inhibit mitochondrial respiratory complex I, thereby contributing to two biochemical processes associated with PD risk. We have assembled a team of experts in analytical biochemistry, neurodegenerative disease and bioinformatics to use a new high-throughput metabolic profiling method coupled to bioinformatics to identify unique metabolic signatures of pesticide exposures and PD development. This powerful methodology is coupled with capabilities for precise analytical determinations of pesticide contents and oxidative stress so that metabolic signatures can provide a direct link between exposure and disease symptoms. Identification of such metabolic signatures could have considerable impact in providing a means for early detection of risk and suggesting novel targets for intervention to prevent or manage disease progression. The metabolomics platform allows detection of 2000 metabolic features in a 10 min analysis of human plasma. Specific Aims are to use this assay to 1) profile the metabolic changes in plasma, cerebrospinal fluid and substantia nigra of mouse models of PD in which chemicals (MPTP, dieldrin) are used to elicit symptoms in wildtype mice, a sensitive mouse line with reduced ability to properly store dopamine (VMAT2-deficient), and a resistant mouse line with increased content of mitochondrial thioredoxin-2; 2) identify metabolic features associated with PD and with pesticide levels in PD and non-PD controls; and 3) develop standardization procedures to allow creation of a cumulative data library for human metabolomic data. Successful completion of these aims will provide key new information concerning the hypothesis that exposure to environmental chemicals create a metabolic platform for PD risk which can be evaluated by clinical metabolomics and used as a basis for early interventions to prevent disease and therapeutic approaches to delay progression.