Motor and Cognitive Health Outcomes in a Mn-Exposed African Community

接触锰的非洲社区的运动和认知健康结果

• 批准号: 9236970
• 负责人: Brad A Racette
• 金额: $ 7.04万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236970
• 关键词: Adult; African; Behavioral; Bioinformatics; Biological Markers; Biological Models; Cell Culture Techniques; Cell model; Chronic; Chronic Disease; Cognitive; Communities; Complex; Data; Disease; Dose; Drosophila genus; Environmental Exposure; Environmental Impact; Epidemiology; Epigenetic Process; Exposure to; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Health; Human; In Vitro; Lead; Link; Manganese; Messenger RNA; MicroRNAs; Modeling; Molecular Profiling; Monitor; Moods; Motor; Neurocognitive; Neurons; Neurotoxins; Ontology; Outcome; Parents; Pathogenesis; Pharmacology; Phenotype; Play; Process; Public Health; Role; Saliva; Sampling; South Africa; System; Technology; Tissues; Toxic effect; Trace Elements; Translations; United States Environmental Protection Agency; Untranslated RNA; Validation; biomarker development; candidate marker; cognitive control; cohort; disturbance in affect; epidemiology study; exosome; exposed human population; genetic approach; human data; in vivo; in vivo Model; insight; miRNA expression profiling; neuropathology; neurotoxic; neurotoxicity; next generation sequencing; novel; parent grant; population based; response; transcriptome; transcriptomics; whole genome

Abstract Manganese (Mn) is an essential trace element and an established neurotoxicant with complex pharmacology. In the parent grant, “Motor and Cognitive Health Outcomes in a Manganese-Exposed African Community,” we are conducting a population-based epidemiology study of Mn-exposed adults living near a large Mn smelter in Meyerton, South Africa, to investigate the association between environmental Mn exposure, at ambient levels below current Environmental Protection Agency regulatory levels, and motor, cognitive control, and mood dysfunction. This ViCTER proposal expands the scope of the parent human epidemiology study by including exploratory biomarker development, and initiating a deeper mechanistic understanding of the negative impact of Mn exposure on neurocognitive functions using in vitro human neuronal cell culture models and in vivo Drosophila Mn exposure models. These new aims will investigate the hypothesis that Mn exposure can lead to poor phenotypic outcomes via epigenetic processes driven by the synthesis and secretion of small, non-coding RNAs, known as micro RNAs (miRNAs). Growing evidence suggests that Mn is directly involved in the synthesis of miRNAs, and that miRNAs play a significant role in the pathogenesis of many chronic diseases, by repressing translation and regulating degradation of their target mRNAs. In this proposal, we take the unique approach of using cellular and Drosophila models of Mn toxicity to identify specific miRNAs associated with Mn exposure in vivo in humans, which will be used to identify specific human miRNAs from across the entire genome that may serve as biomarkers of Mn exposure and related health outcomes. We will also explore and confirm gene targets of the identified miRNA biomarkers. Ultimately, this ViCTER will generate novel data that will link environmental Mn exposure to biomarkers that could be used to monitor exposed communities and may contribute to a better understanding of mechanisms of Mn-induced human neurotoxicity. The expanded scope of this proposal will provide unprecedented bidirectional data from humans and model systems to investigate this important and common neurotoxicant.

抽象的 锰（MN）是具有复杂药理学的既定痕量元素，也是已建立的神经毒性。 在父母的赠款中，“在暴露于锰的非洲社区中的运动和认知健康成果”，我们 正在进行一项基于人群的流行病学研究，对居住在大型Mn冶炼厂附近的MN暴露成年人 南非的迈尔顿（Meyerton），调查环境MN暴露之间的关联 低于当前环境保护局的监管水平，运动，认知控制和情绪 功能障碍。这项Victer提案通过包括 探索性生物标志物的开发，并对负面影响提出更深入的机械理解 使用体外人神经元细胞培养模型和体内的MN暴露于神经认知功能的暴露 果蝇MN暴露模型。这些新目标将调查MN暴露会导致的假设 通过小型非编码的合成和分泌驱动的表观遗传过程的表型结果不良 RNA，称为微RNA（miRNA）。越来越多的证据表明，MN直接参与 miRNA的合成，miRNA在许多慢性疾病的发病机理中起着重要作用， 抑制其目标mRNA的翻译和调节降解。在此提案中，我们采用独特的 使用MN毒性的细胞和果蝇模型来鉴定与MN相关的特定miRNA 人体中的体内暴露，将用于从整个中识别特定的人类miRNA 可以用作MN暴露和相关健康结果的生物标志物的基因组。我们还将探索和 确认已鉴定的miRNA生物标志物的基因靶标。最终，这个Victer将生成新的数据 将将环境MN暴露与可用于监视暴露社区和的生物标志物联系起来 可能有助于更好地理解MN引起的人类神经毒性的机制。扩展 该提案的范围将为人类和模型系统提供前所未有的双向数据 研究这种重要且常见的神经毒性。