MicroRNAs, ER Stress and Arsenic Neurotoxicity

MicroRNA、内质网应激和砷神经毒性

• 批准号: 10331345
• 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/10331345
• 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; Lung diseases; Malignant Neoplasms; Measures; Mediating; MicroRNAs; Molecular; Neurocognitive; Neurological outcome; Pathway interactions; Phenotype; Play; Poison; Population; Predisposition; Prevalence; Proliferating; Proteins; Public Health; Reporter; Reporting; 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/antagonist; 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，可导致多种疾病，包括 癌症、心血管疾病、糖尿病、呼吸系统疾病和神经系统疾病。由于暴露于 大脑发育的早期阶段对神经认知功能具有长期影响。虽然 流行病学研究报告，产前砷暴露与神经发育受损有关， 早期大脑发育对砷暴露敏感性的分子机制仍然很差 明白最近，内质网（ER）应激通过在ER中积累未折叠的蛋白质， 随后未折叠蛋白反应（UPR）激活已成为As- 介导的不良神经学结局。我们的全基因组CRISPR筛选鉴定出新型ER抑制剂 包括microRNA（miR）-124在内的As诱导的ER应激的影响，并表明miR-124对As-124具有保护作用。 诱导ER应激/UPR信号传导。有趣的是，miR-124是大脑中最丰富的miR之一， 在神经分化和增殖中起重要作用。利用现有的全基因组数据 环境流行病学队列的关联研究，我们进一步表明，miR-124多态性 与儿童的神经系统结果显著相关，可能通过与As暴露的相互作用。 基于这些研究，我们推测As干扰了神经干细胞的ER应激和UPR信号通路 细胞影响神经干细胞功能和损害早期脑发育。我们进一步假设 miR-124保护免受砷诱导的干扰，以恢复功能和稳态， 在神经干细胞中。为了验证这些假设，我们提出了一个高度综合的项目， 培养的神经干细胞和人类环境和遗传的分子机制研究 砷暴露儿童的流行病学研究：目的1）探讨砷引起的内质网应激对神经干细胞的影响 目的2）阐明miR-124保护神经细胞免受As毒性的机制。 3）确定miR-124变体与儿童神经发育的功能关联 暴露于As。拟议的研究将影响环境卫生领域的关键影响， 首要任务，无处不在的有毒物质对儿童早期大脑发育的影响。这项研究的结果将建立 砷诱导的内质网应激/UPR信号通路是砷对神经干细胞毒性作用的重要机制 功能和神经发育，并可能确定小microRNA作为预防和治疗的新靶点。 治疗干预对儿童砷暴露的有害影响。