EV miRs in cognitive function decline associated with early life metal exposure

EV miRs与早期金属暴露相关的认知功能下降

基本信息

批准号：
10332730
负责人：
Quan Lu
金额：
$ 32.2万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-21 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10332730
关键词：
3-Dimensional Affect Age-Months Aging Alzheimer&apos s Disease Anatomy Arsenic Biological Biological Assay Biological Markers Blood Brain Cadmium Cell physiology Cells Cognitive Cognitive aging Communities Complement Data Data Analyses Development Disease Elderly Encapsulated Environmental Exposure Epidemiology Exposure to Fetal Tissues Gene Expression Goals Health Human Impaired cognition Individual Laboratories Lead Life Link Lipid Bilayers Liquid substance Mammalian Cell Manganese Mediating Mediator of activation protein Membrane Messenger RNA Metal exposure Metals Methodology Methods MicroRNAs Molecular Mus Neurodegenerative Disorders Neurons Organoids Outcome Pathway interactions Plasma Research Role Signaling Molecule Source Superfund Testing Training and Education Translational Research Translations Vesicle Water Work base brain cell cognitive function cohort community engagement contaminated water data management drinking water early life exposure education research extracellular extracellular vesicles human disease human fetal brain in vivo intercellular communication molecular marker mouse model multidisciplinary nerve stem cell neurobehavioral neuroimaging neurotoxicity novel marker novel strategies nuclease postnatal period prenatal remediation response self-renewal social stem cell function superfund site toxicant training opportunity transcriptome sequencing water sampling

项目摘要

PROJECT SUMMARY/ ABSTRACT Early-life exposure to Superfund metal toxicants such as lead (Pb), arsenic (As), cadmium (Cd) and Manganese (Mn) has been associated with worse cognitive function during aging and is suspected of contributing to the development of neurodegenerative diseases, such as Alzheimer’s disease. However, the biological mechanisms underlying the associations remain poorly understood. Mammalian cells, including neurons and neural stem cells, secrete into the extracellular milieu a variety of tiny membrane-encapsulated vesicles. These extracellular vesicles (EVs) contain functional signaling molecules that can be taken up by recipient cells to mediate intercellular communication. One such group of signaling molecules is microRNAs, which function as master tuners of gene expression by degrading target mRNA and/or inhibiting translation of the message. Since EVs are encapsulated by a lipid bilayer membrane, molecules such as microRNAs enclosed in the vesicles are protected from nuclease-mediated degradation and thus are thus very stable. As a result, EV microRNAs can be easily detected and quantitated in biological fluids such as plasma/serum and have been used as novel biomarkers for a variety of human diseases. Although some limited studies have explored the role of EV microRNAs in neural cells, no studies have examined the role of EV microRNAs on cognitive function in the context of environmental exposures such as metal toxicants. We hypothesize that metal exposures in early life alter EV microRNAs in the brain and that these changes in EV microRNAs affect the function of neurons and neural stem cells to accelerate cognitive aging. We propose three interconnected Specific Aims to test this hypothesis. Aim 1 will determine the effects of exposures to individual metal exposures (Pb, As, Mn, and Cd) as well as “real-world” metal mixtures (pre- and post-remediation water samples collected at the San Luis Valley Superfund site) on developing human fetal brain organoids. Aim 2 will determine the effects of early-life exposure to individual metals (Pb and As) as well as to the real-world metal mixtures on EV miRs and the cognitive function of mice later in life. Aim 3 will determine the functional role of selected EV microRNAs in modulating functions of brain organoids and cognitive function in mice. Our highly multidisciplinary study integrating mouse models, human epidemiology, and functional cellular studies seeks to establish EV microRNAs not only as novel biomarkers for metal exposure-related cognitive function, but also as a mechanistic basis for metal- induced neurotoxicity and cognitive impairment. This project links with the MEMCARE-SRC by complementing human studies in Project 1 and seeking to identify biologic mechanisms for health effects of water contamination at Superfund sites.

项目概要/摘要生命早期接触超级基金金属毒物，如铅 (Pb)、砷 (As)、镉 (Cd) 和锰 (Mn) 与衰老过程中认知功能较差有关，并且被怀疑有助于神经退行性疾病的发展，例如阿尔茨海默病。这种关联背后的生物学机制仍然知之甚少，包括哺乳动物细胞。神经元和神经干细胞，分泌到细胞外环境中的各种微小的膜封装这些细胞外囊泡 (EV) 含有可被细胞吸收的功能性信号分子。受体细胞介导细胞间通讯的一组信号分子是。 microRNA，通过降解靶 mRNA 和/或作为基因表达的主调谐器由于 EV 被脂质双层膜包裹，分子被抑制。例如封闭在囊泡中的 microRNA 受到保护，免受核酸酶介导的降解，因此因此，EV microRNA 非常稳定，可以在生物体液中轻松检测和定量。例如血浆/血清，并已被用作多种人类疾病的新型生物标志物。一些有限的研究探索了 EV microRNA 在神经细胞中的作用，但没有研究检验过 EV microRNA 在金属等环境暴露情况下对认知功能的作用我们认为生命早期接触的金属会改变大脑中的 EV microRNA，而这些 EV microRNA 的变化影响神经元和神经干细胞的功能以加速认知我们提出了三个相互关联的具体目标来检验这一假设，目标 1 将确定。暴露于单个金属（Pb、As、Mn 和 Cd）以及“现实世界”金属的影响混合物（在圣路易斯谷超级基金现场收集的修复前和修复后水样）开发人类胎儿大脑类器官，目标 2 将确定生命早期暴露对个体的影响。金属（Pb 和 As）以及 EV miR 上的现实世界金属混合物以及认知功能目标 3 将确定选定的 EV microRNA 在调节功能中的功能作用。我们的高度多学科研究整合了小鼠的大脑类器官和认知功能。模型、人类流行病学和功能细胞研究旨在建立 EV microRNA，不仅作为与金属暴露相关的认知功能的新型生物标志物，同时也作为金属暴露的机制基础诱发的神经毒性和认知障碍该项目通过以下方式与 MEMCARE-SRC 联系起来。补充项目 1 中的人类研究，并寻求确定对健康影响的生物机制超级基金地点的水污染。