CHOROID PLEXUS AS A TARGET IN METAL-INDUCED NEUROTOXICITY

脉络丛作为金属引起的神经毒性的靶点

• 批准号: 8231425
• 负责人: WEI ZHENG
• 金额: $ 39.2万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231425
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyotrophic Lateral Sclerosis; Animals; Blood; Blood - brain barrier anatomy; Blood capillaries; Brain; Brain region; Carrier Proteins; Cell Line; Cells; Cerebrospinal Fluid; Collaborations; Copper; Data; Epithelial; Epithelium; Equilibrium; Exposure to; Fluorescence; Foundations; Funding; Goals; Grant; Homeostasis; Human; In Vitro; Lead; Location; Manganese; Metals; Modeling; Molecular; Neuraxis; Neurodegenerative Disorders; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Perfusion; Physics; Prion Diseases; Process; Production; Rattus; Regulation; Relative (related person); Research; Research Project Grants; Roentgen Rays; Role; SLC11A2 gene; Saliva; Scanning; Small Interfering RNA; Structure of choroid plexus; Surface; Synchrotrons; System; Techniques; Testing; Time; Tissues; Toxic Environmental Substances; Western Blotting; Work; base; blood cerebrospinal fluid barrier; brain tissue; capillary; cohort; design; in vivo; inhibitor/antagonist; insight; lead exposure; neurotoxicity; novel; professor; public health relevance; stable cell line; three-dimensional modeling; toxic metal; trafficking; uptake

DESCRIPTION (provided by applicant): Altered brain copper (Cu) homeostasis has been associated with idiopathic Parkinson's disease (IPD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Prion disease. We have recently discovered that Cu levels in blood and saliva of Mn-exposed workers from human cohorts are significantly increased, and so are the Cu levels in the CSF and brain tissues of Mn- exposed animals. While the presence of transporters possibly responsible for Cu transport in brain barriers such as Cu transport protein-1 (Ctr1), divalent metal transporter-1 (DMT1) and ATP7A has been demonstrated, how Cu is transported by these transporters in brain barriers and by what mechanism exposure to manganese (Mn) alters the expression and function of these transporters are unknown. This research project is designed to test the hypothesis that the choroid plexus, a brain tissue forming a barrier between the blood and cerebrospinal fluid (CSF), regulates Cu transport between the blood and CSF through the critical transporters; exposure to Mn alters the functions of these transporters, leading to a distorted Cu homeostasis in the CSF. To test this hypothesis, we have designed 4 specific aims. In Aim 1, we will determine if subchronic exposure to Mn in a rat model alters the expression of Ctr1, DMT1 and ATP7A in blood-brain barrier (BBB) and blood-CSF barrier (BCB), leading to an increased influx of Cu from the blood to brain parenchyma and a decreased Cu efflux from the CSF to blood. In Aim 2, we will reveal if Ctr1 and DMT1 coordinate the Cu uptake on the surface of the BBB and BCB and if Mn exposure disrupts these processes, leading to cellular overload of Cu by the brain barrier cells. Aim 3 is designed to investigate if the intracellular trafficking of ATP7A determines the direction of Cu transport by the BCB and if Mn exposure, by acting on ATP7A, may alter the direction of Cu transport between the blood and the CSF. Finally, in Aim 4, we will use the synchrotron rapid scanning X-ray fluorescence (RS-XRF) technique, by collaboration with the professor in Purdue's Physics department, to establish 3D model to simultaneously localize and quantify Cu, Fe, Mn and Zn in brains of Mn-exposed rats. The studies proposed in this application will define the inter-relationship between Ctr1, DMT1 and ATP7A in brain barriers with regard to their subcellular locations, roles in transport of Cu, and their regulation as affected by Mn exposure; will provide the insight into the molecular mechanism by which Mn affects Cu transport by brain barriers; and will ultimately provide a better understanding of Cu dysregulation-related neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Altered brain copper (Cu) homeostasis has been associated with idiopathic Parkinson's disease (IPD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Prion disease. This project will uncover how Cu is transferred in and out of the brain and how exposure to environmental toxicant manganese (Mn) interferes with the Cu balance in brain, which in turn causes the degenerative manganese parkinsonism.

描述（由申请人提供）：改变的脑铜（CU）稳态与特发性帕金森氏病（IPD），阿尔茨海默氏病（AD），肌萎缩性侧面硬化症（ALS）和Prion病有关。我们最近发现，来自人类人群的MN暴露工人的血液和唾液水平显着增加，MN暴露动物的CSF和脑组织中的CU水平也有所增加。虽然已经证明了运输蛋白可能负责CU转运蛋白1（CTR1），二价金属转运蛋白1（DMT1）和ATP7A等脑屏障中的CU传输的存在，但这些转运蛋白如何在脑屏障中运输CU，以及通过对锰（MN）暴露于这些机械的表达和功能的型号。该研究项目旨在检验以下假设：脉络丛，即脑组织在血液和脑脊液和脑脊液之间形成屏障（CSF），可通过关键转运蛋白调节血液和CSF之间的CU转运。暴露于MN会改变这些转运蛋白的功能，从而导致CSF中的Cu稳态扭曲。为了检验这一假设，我们设计了4个具体目标。在AIM 1中，我们将确定在大鼠模型中接触MN是否会在血脑屏障（BBB）和血脑屏障屏障（BCB）中改变Ctr1，DMT1和ATP7A的表达，从而导致Cu从血液到脑静脉内的CU涌入，并减少了Cu efflux的Cu Ferflux。在AIM 2中，我们将揭示CTR1和DMT1是否协调BBB和BCB表面上的Cu摄取，以及MN暴露是否破坏了这些过程，从而导致脑屏障细胞的细胞过载CU。 AIM 3旨在研究ATP7A的细胞内运输是否决定了BCB运输的CU转运方向，如果MN暴露，通过作用于ATP7A，可能会改变血液和CSF之间的Cu转运方向。最后，在AIM 4中，我们将通过与普渡大学物理学的教授合作建立3D模型，以同时定位和量化CU，FE，FE，MN和ZN，MN在大脑中，MN呈现大鼠的MN大鼠。本应用中提出的研究将在脑屏障中定义CTR1，DMT1和ATP7A之间的相互关系，这些研究在其亚细胞位置，CU运输中的作用以及受到MN暴露的影响；将提供有关MN影响脑屏障Cu转运的分子机制的见解；并最终将更好地理解与CU失调相关的神经退行性疾病。 公共卫生相关性：改变的脑铜（CU）稳态与特发性帕金森氏病（IPD），阿尔茨海默氏病（AD），杏仁核外侧硬化症（ALS）和prion病有关。该项目将揭示CU如何进入大脑和外出，以及暴露于环境有毒锰（MN）如何干扰大脑中的Cu平衡，这又导致退化性锰帕金森氏症。