Gene-Environment Interactions in Neurodegeneration: Role of Efflux Transporters

神经变性中的基因-环境相互作用：外排转运蛋白的作用

基本信息

批准号：
9172327
负责人：
Lauren M Aleksunes
金额：
$ 25.01万
依托单位：
NORTHEAST OHIO MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9172327
关键词：
ABCB1 gene Affect Applications Grants Blood - brain barrier anatomy Brain Capillary Endothelial Cell Catalytic Domain Cells Chemicals Chronic Clinical Complement Complex Cultured Cells Data Degenerative Disorder Disease Dose Down-Regulation Engineering Environmental Exposure Environmental Risk Factor Epidemiologic Studies Epidemiology Etiology Event Exhibits Exposure to Genes Genetic Genetic Polymorphism Genetic Variation Health Herbicides Human In Vitro Individual Inflammation Inflammatory Lead Link Lipopolysaccharides Mediating Messenger RNA Microglia Modeling Mus NADPH Oxidase Nerve Degeneration Neurons Orthologous Gene P-Glycoprotein Paraquat Parkinson Disease Pathogenesis Pathway interactions Patients Pesticides Predisposition Proteins Regulation Research Risk Risk Factors Rodent Role Small Interfering RNA Substantia nigra structure Techniques Testing Therapeutic Intervention Toxic effect Transgenic Mice Tumor Necrosis Factor Receptor Up-Regulation Xenobiotics base cytokine dopaminergic neuron gene environment interaction genetic variant immortalized cell in vivo in vivo Model inhibitor/antagonist insight killings loss of function nervous system disorder neuroinflammation neurotoxicity novel overexpression pesticide exposure pesticide induced neurotoxicity prevent translational study

项目摘要

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.

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，据估计影响美国至少 100 万人，全球超过 1000 万人。 PD 是一种复杂的疾病，没有任何单一基因与很大比例的病例相关，这表明环境因素或基因-环境相互作用可能导致病因或临床表现。在接触农药的帕金森病患者中，更频繁地观察到外源性转运蛋白多药耐药蛋白 1（MDR1，也称为 P-糖蛋白）的多态性降低了其功能。这一发现提出了一种可能性，即 MDR1 功能的改变会增加接触农药的人患 PD 的风险。由于 MDR1 对于从大脑中排出化学物质至关重要，因此我们假设 MDR1 主动将农药从大脑中排出，并且这种转运蛋白的遗传或后天缺陷可能会导致神经变性。我们的主要研究目的是确定 MDR1 是一种主要的外排转运蛋白，负责从大脑中清除农药，包括与多巴胺能神经变性有关的除草剂百草枯，并防止神经变性。这很重要，因为 1) MDR1 在人脑毛细血管内皮细胞和其他神经元细胞中显着表达，2) MDR1 的多态性与接触农药的患者患 PD 的风险增加有关，3) 神经炎症与接触农药的患者患 PD 的风险增加有关。包括 PD 在内的多种退行性疾病已被发现会下调 MDR1。因此，预计这些数据将有助于更好地理解MDR1的遗传和炎症调节，以及MDR1在农药滞留在大脑中的潜在作用，并使我们能够确定基因-环境的机制。 MDR1、农药和神经变性之间的相互作用。