MicroRNAs, ER Stress and Arsenic Neurotoxicity

MicroRNA、内质网应激和砷神经毒性

• 批准号: 10341234
• 负责人: Hae-ryung Park
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341234
• 关键词: ATF6 gene; Adverse effects; Affect; Air; Apoptosis; Apoptotic; Arsenic; Bangladesh; Binding; Brain; CRISPR screen; Cardiovascular Diseases; Cell Line; Child; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Diabetes Mellitus; Disease; Disease Outcome; Endoplasmic Reticulum; Environment; Environmental Epidemiology; Environmental Health; Epidemiology; Exposure to; Food; Genes; Genetic Polymorphism; Genotype; Homeostasis; Human; Impairment; In Vitro; Knock-out; Lead; Link; Malignant Neoplasms; Measures; Mediating; MicroRNAs; Molecular; Neurocognitive; Neurological outcome; Pathway interactions; Phenotype; Play; Poison; Population; Predisposition; Prevalence; Proliferating; Proteins; Public Health; Reporter; Reporting; Respiratory Disease; Role; Signal Transduction; Small RNA; Testing; Therapeutic Intervention; Toxic effect; Untranslated Regions; Variant; arm; base; cohort; disease registry; drinking water; endoplasmic reticulum stress; epidemiology study; exposure route; functional restoration; genetic epidemiology; genome wide association study; genome-wide; indexing; inhibitor; loss of function; misfolded protein; nerve stem cell; neurobehavior; neurodevelopment; neuron loss; neuronal survival; neurotoxicity; novel; overexpression; precise genome editing; prenatal; preventive intervention; protective effect; protein folding; reconstitution; relating to nervous system; response; self-renewal; stem cell function; stem cell model; toxicant; transcription factor CHOP

ABSTRACT Exposure to arsenic (As) is a serious public health concern, contributing to a myriad of diseases including cancer, cardiovascular disease, diabetes, respiratory disease, and neurological outcomes. As exposure during the early stages of brain development has long-lasting effects on neurocognitive function. Although epidemiological studies report that prenatal As exposure is associated with impaired neurodevelopment, the molecular mechanisms underlying the susceptibility of early brain development to As exposure remain poorly understood. Recently, endoplasmic reticulum (ER) stress by accumulation of unfolded proteins in the ER and subsequent activation of unfolded protein response (UPR) have emerged as a potential mechanism for As- mediated adverse neurological outcomes. Our genome-wide CRISPR screen identified novel ER suppressors of As-induced ER stress including microRNA(miR)-124 and indicated that miR-124 is protective against As- induced ER stress/UPR signaling. Interestingly, miR-124 is one of the most abundant miRs in the brain and plays important roles in neural differentiation and proliferation. Using data from existing genome-wide association studies of an environmental epidemiological cohort, we further showed that miR-124 polymorphism significantly associates with neurological outcomes in children, possibly through interaction with As exposure. Based on these studies, we hypothesize that As perturbs ER stress and UPR signaling in neural stem cells to affect neural stem cell function and to impair early brain development. We further hypothesize that miR-124 protects against As exposure-induced perturbation to restore function and homeostasis in neural stem cells. To test these hypotheses, we propose a highly integrative project that combines molecular mechanistic studies in cultured neural stem cells and human environmental and genetic epidemiology in children exposed to As: Aim 1) Investigate the role of As-induced ER stress on neural stem cell function; Aim 2) Elucidate the mechanisms through which miR-124 protects against As toxicity in neural stem cells; Aim 3) Determine the functional association of miR-124 variants with neurodevelopment in children exposed to As. The proposed study will impact the field of environmental health by keying in on the impact of a top priority, ubiquitous toxicant As on early brain development in children. Results from this study will establish As-induced ER stress/UPR signaling as a crucial mechanism for the adverse effects of As on neural stem cell function and neurodevelopment, and may identify small microRNAs as a novel target for preventative and therapeutic interventions against detrimental effects of As exposure in children.

摘要 接触砷(As)是一个严重的公共卫生问题，导致无数疾病，包括 癌症、心血管疾病、糖尿病、呼吸系统疾病和神经后果。作为暴露在 大脑发育的早期阶段对神经认知功能有长期的影响。虽然 流行病学研究报告称，产前接触砷与神经发育受损有关， 大脑早期发育对砷暴露易感性的分子机制仍不清楚 明白了。最近，内质网(ER)通过在内质网和内质网中积累未折叠蛋白而应激。 随后未折叠蛋白反应(UPR)的激活已成为AS的一种潜在机制。 导致不良的神经后果。我们的全基因组CRISPR筛查发现了新的ER抑制因子 包括microRNA(MiR)-124在内的As诱导的内质网应激的研究结果表明，miR-124对As诱导的ER应激具有保护作用。 诱导内质网应激/UPR信号传导。有趣的是，miR-124是大脑中含量最丰富的miR之一， 在神经分化和增殖中起重要作用。使用现有全基因组的数据 对一个环境流行病学队列的关联性研究，我们进一步表明miR-124基因多态性 与儿童的神经学结果显著相关，可能是通过与AS暴露的相互作用。 基于这些研究，我们假设AS扰乱了神经干细胞中的内质网应激和UPR信号 影响神经干细胞功能和损害早期大脑发育的细胞。我们进一步假设 MiR-124防止AS暴露诱导的扰动以恢复功能和内稳态 在神经干细胞中。为了检验这些假设，我们提出了一个高度整合的项目，它结合了 神经干细胞培养的分子机制研究与人类环境和遗传 砷暴露儿童的流行病学：目的1)研究砷诱导的内质网应激对神经干细胞的作用 细胞功能；目的2)阐明miR-124保护神经抗AS毒性的机制 干细胞；目的3)确定miR-124变异与儿童神经发育的功能联系 暴露在砷中。这项拟议的研究将通过键入一种 当务之急，无处不在的有毒物质对儿童早期大脑发育的影响。这项研究的结果将确定 砷诱导的内质网应激/UPR信号转导是砷对神经干细胞不利影响的重要机制 功能和神经发育，并可能确定小的microRNAs作为预防和 针对儿童砷暴露有害影响的治疗干预。