Gene-Environment Interactions in Neurodegeneration: Role of Efflux Transporters

描述（由申请人提供）：帕金森病（PD）是一种慢性退行性神经系统疾病，估计在美国影响至少100万人，全球超过1000万人。PD是一种复杂的疾病，没有单一基因与显著比例的病例相关，这表明环境因素或基因-环境相互作用可能对病因或临床表现有影响。外源转运体多药耐药蛋白1 （MDR1，也称为p糖蛋白）的多态性降低了其功能，这在暴露于农药的PD患者中更为常见。这一发现提高了MDR1功能改变增加农药暴露人群患帕金森病风险的可能性。由于MDR1在将化学物质从大脑中排出方面至关重要，我们假设MDR1主动将农药从大脑中排出，这种转运体的遗传或获得性缺乏可能导致神经退行性变。我们的主要研究目标是确定MDR1作为主要的外排转运体，负责从大脑中清除农药，包括与多巴胺能神经生成有关的除草剂百草枯，并防止神经退行性变。这很重要，因为1)MDR1在人脑毛细血管内皮细胞和其他神经细胞中显著表达，2)MDR1的多态性与农药暴露患者PD风险增加有关，3)与PD等多种退行性疾病相关的神经炎症已被发现下调MDR1。因此，我们期望这些数据能够更好地理解MDR1的遗传和炎症调控，以及MDR1在农药在大脑中的保留中的潜在作用，并使我们能够确定MDR1、农药和神经退行性变之间基因-环境相互作用的机制。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a chronic, degenerative neurological disorder that is estimated to affect at least 1 million individuals in the U.S. and ovr 10 million worldwide. PD is a complex disorder, and no single gene has been linked to a significant percentage of cases, suggesting that environmental factors or gene-environment interactions may contribute to the etiology or clinical manifestation. A polymorphism in the xenobiotic transporter Multidrug resistance protein 1 (MDR1, also known as P-glycoprotein) that reduces its function has been observed more frequently in PD patients who were exposed to pesticides. This finding raises the possibility that altered MDR1 function increases the risk for PD in people exposed to pesticides. Since MDR1 is critically important in expelling chemicals from the brain, we have hypothesized that MDR1 actively effluxes pesticides from the brain and genetic or acquired deficiency in this transporter may contribute to neurodegeneration. Our main research aim is to identify MDR1 as a primary efflux transporter responsible for removing pesticides, including the herbicide paraquat that has been linked to dopaminergic neurodgeneration, from the brain and protecting against neurodegeneration. This is significant because 1) MDR1 is prominently expressed in human brain capillary endothelial cells and other neuronal cells, 2) a polymorphism in MDR1 has been associated with increased risk of PD in patients exposed to pesticides, and 3) neuroinflammation, which is associated with multiple degenerative diseases including PD, has been found to down-regulate MDR1. Therefore, it is expected that these data will provide a better understanding of the genetic and inflammatory regulation of MDR1 as well as the potential role of MDR1 in the retention of pesticides in the brain, and will allow us to determine the mechanism of gene-environment interactions between MDR1, pesticides, and neurodegeneration.