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) 是一种必需的微量元素，也是一种具有复杂药理学的神经毒剂。 在家长资助“锰暴露非洲社区的运动和认知健康结果”中，我们 正在对居住在大型锰冶炼厂附近的接触锰的成年人进行一项基于人群的流行病学研究 南非迈耶顿调查环境水平锰暴露之间的关联 低于当前环境保护局监管水平以及运动、认知控制和情绪 功能障碍。 ViCTER 提案扩大了人类流行病学研究的范围，包括 探索性生物标志物开发，并开始对负面影响进行更深入的机制理解 使用体外人类神经元细胞培养模型和体内锰暴露对神经认知功能的影响 果蝇锰暴露模型。这些新目标将研究锰暴露可能导致的假设 由小型非编码基因的合成和分泌驱动的表观遗传过程导致表型结果不佳 RNA，称为微小 RNA (miRNA)。越来越多的证据表明锰直接参与 miRNA 的合成，并且 miRNA 在许多慢性疾病的发病机制中发挥着重要作用， 抑制翻译并调节其目标 mRNA 的降解。在这个提案中，我们采用了独特的 使用锰毒性的细胞和果蝇模型来识别与锰相关的特定 miRNA 的方法 人类体内暴露，这将用于识别整个人体中的特定人类 miRNA 基因组可作为锰暴露和相关健康结果的生物标志物。我们还将探索和 确认已识别的 miRNA 生物标志物的基因靶标。最终，这个 ViCTER 将生成新颖的数据 将把环境中的锰暴露与生物标志物联系起来，这些生物标志物可用于监测暴露的社区和 可能有助于更好地理解锰引起的人类神经毒性的机制。扩展后的 该提案的范围将提供前所未有的来自人类和模型系统的双向数据 研究这种重要且常见的神经毒物。