Mechanisms of Manganese Neurotoxicity

锰神经毒性机制

基本信息

批准号：
8960347
负责人：
Michael Aschner
金额：
$ 95.49万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8960347
关键词：
Biological Assay Biological Models Biology Body Burden Caenorhabditis elegans Cell Line Chelating Agents Chemicals Corpus striatum structure Data Disease Dissection Enhancers Environmental Risk Factor Etiology Exhibits Experimental Designs Fluorescence Funding Fura-2 Genetic Goals Health Homologous Gene Human In Vitro Institutes Knowledge Lead Libraries Light Manganese Mediating Membrane Potentials Metal exposure Methods Midbrain structure Mitochondria Modality Modeling Molecular Molecular Target Morphology Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Outcome Measure Oxidative Stress PARK2 gene Parkinson Disease Pathway interactions Patients Phenotype Play Predisposition Property Prosencephalon RNA Interference RNA interference screen Research Risk Role Signal Transduction Substantia nigra structure System Testing Therapeutic Toxic effect Translating base biological adaptation to stress biological systems cellular targeting clinically relevant disorder control dopaminergic neuron early onset environmental stressor gene environment interaction genetic risk factor high throughput screening in vivo induced pluripotent stem cell innovation interdisciplinary approach mitochondrial dysfunction nerve stem cell nervous system disorder neurotoxic neurotoxicity novel novel therapeutics research study response small molecule stem cell technology stressor tool trafficking trait translational study uptake

项目摘要

DESCRIPTION (provided by applicant): Manganese (Mn) is a potent neurotoxin. We hypothesize that PARK2, a strong Parkinson's disease (PD) genetic risk factor, alters neuronal vulnerability to modifiers of cellular Mn status, particularly at the level of mitochondrial dysfunction and oxidative stress. The long-term goal of this research is to elucidate the basis of Mn-induced neurotoxicity and to identify mechanistic-based neuroprotective strategies to mitigate human Mn exposure risk. Our approach will utilize a novel high-throughput assay of intracellular Mn levels to identify small molecule modifiers of cellular Mn status and neurotoxicity. Genetic modifiers of Mn transport and toxicity will be defined and translational studies of existing and newly identified genetic and small molecule modifiers of Mn toxicity will be performed utilizing a primary human neuronal model system based upon human induced pluripotent stem cell (hiPSC) technology. Aim 1 will identify lead compounds that alter neuronal Mn transport and toxicity in vitro using striatal and mesencephalic murine neuronal cell lines and in vivo using C. elegans. Aim 2 will delineate functional pathways that regulate Mn transport and toxicity in vivo and in vitro. Specific Aim 3 will test the hypothesis that human neuronal models of PD exhibit increased sensitivity to perturbations of cellular Mn status. These specific aims hold the promise of delineating common initiator signals for the modulation of Mn neurotoxicity, shedding light on mechanisms and susceptibility associated with exposure to this metal. This dual-PI proposal is bolstered by its use of innovative state-of-the-art complimentary approaches in diverse model systems.

描述（由申请人提供）：锰（MN）是一种有效的神经毒素。我们假设PARK2是一种强大的帕金森氏病（PD）遗传危险因素，会改变神经元脆弱性对细胞MN状态的修饰，尤其是在线粒体功能障碍和氧化应激水平上。这项研究的长期目标是阐明MN诱导的神经毒性的基础，并确定基于机械的神经保护策略，以减轻人类MN暴露风险。我们的方法将利用细胞内MN水平的新型高通量测定法确定细胞MN状态和神经毒性的小分子修饰剂。将定义MN转运和毒性的遗传修饰符，并利用基于人类诱导的多能干细胞（HIPSC）技术的原代人神经元模型系统进行现有和新鉴定的MN毒性的遗传和小分子修饰剂的翻译研究。 AIM 1将鉴定使用纹状体和中脑鼠神经元细胞系在体外改变神经元MN转运和毒性的铅化合物，并使用秀丽隐杆线虫在体内。 AIM 2将描述调节体内和体外中Mn转运和毒性的功能途径。具体目标3将检验以下假设：PD的人类神经元模型表现出对细胞MN状态扰动的敏感性。这些特定的目的有望描述MN神经毒性调节的共同引发剂信号，从而阐明了与暴露于这种金属相关的机制和易感性。该双PI提案通过使用不同模型系统中创新的免费免费方法来加强该提案。