MicroRNA pathway in mechanisms of nanoparticles neurotoxicity

纳米颗粒神经毒性机制中的微小RNA途径

基本信息

批准号：
8035758
负责人：
Alexander K. Murashov
金额：
$ 40.43万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-24 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035758
关键词：
MicroRNA pathway mechanisms nanoparticles neurotoxicity

项目摘要

DESCRIPTION (provided by applicant): Recent observations have demonstrated that nanomaterials may be toxic to human tissue and cell cultures, resulting in oxidative stress, inflammatory cytokine production and cell death. While the ability of nano-scaled particulate matter is known to cause a range of problems in respiratory system, recent observations suggest that the nervous system may be vulnerable as well. In particular, it was shown that nanoparticles can penetrate the blood-brain barrier affecting brain signaling linked to Alzheimer's and Parkinson's diseases, and decrease in cognitive function. However, the mechanism of nanomaterials toxicity on the nervous system has been poorly investigated. A significant question remaining to be addressed is how nanoparticles trigger changes in the nerve cells, and what can be done to early detect these deffects. Recent evidence suggests that microRNAs (miRNAs), small non-coding RNAs that regulate gene expression, may be an important prognostic factor in neurodegeneration caused by environmental exposures. While dysregulation of miRNAs has been observed in toxicological and neurological conditions, no mechanistic studies have been done on the role of miRNAs in nanotoxicity. One category of nanomaterial includes carbon nanotubes (CNTs), which are allotropes of carbon with a cylindrical nanostructure. These cylindrical structures have novel properties that make them useful in many applications in nanotechnology, electronics, optics, as well as in medicine. Their final usage, however, may be limited by their potential toxicity. In the current application, we hypothesize that exposure to CNTs will cause dysregulation of miRNAs in neuronal cells and will negatively impact neuronal function. Therefore, the specific aims for the two-year period are: 1) Determine impact of "direct" CNTs exposure on neuronal cultures in vitro, and "indirect" impact on peripheral neuron regeneration following respiratory CNTs exposure in vivo. 2) Characterize miRNA expression signature in neuronal cells in response to "direct" and "indirect" CNTs exposures. 3) Investigate if miRNAs depletion will make neuron regeneration more vulnerable to CNTs exposures by deleting Dicer in vitro and in vivo. The experiments in this application address clinically important question of CNTs neurotoxicity. The proposed research will be essential to establish a foundation for developing miRNA- based methods for diagnosis, prognosis and treatment of CNTs-associated health risks. The long-term objectives of this investigation are to elucidate role of miRNAs in mechanisms underlying the neurotoxicity of CNTs, to provide research opportunities for undergraduate and graduate students, and to provide data on which to establish future R01 grant applications. PUBLIC HEALTH RELEVANCE: The experiments in this application address clinically important question of epigenetic mechanisms of nanoparticle neurotoxicity. The proposed research will advance our understanding of the role of the microRNA pathway in mediating effects of nanoparticles on the nervous system, and will help to establish a foundation for developing methods for diagnosis, prognosis and treatment of nanoparticle associated health problems.

描述（由申请人提供）：最近的观察表明，纳米材料可能对人体组织和细胞培养物有毒，导致氧化应激、炎症细胞因子的产生和细胞死亡。虽然已知纳米级颗粒物会导致呼吸系统出现一系列问题，但最近的观察表明，神经系统也可能很脆弱。特别是，研究表明，纳米颗粒可以穿透血脑屏障，影响与阿尔茨海默氏症和帕金森氏病相关的大脑信号传导，并导致认知功能下降。然而，纳米材料对神经系统的毒性机制尚不清楚。仍有待解决的一个重要问题是纳米颗粒如何引发神经细胞的变化，以及如何尽早发现这些缺陷。最近的证据表明，微小RNA（miRNA），即调节基因表达的小非编码RNA，可能是环境暴露引起的神经退行性变的重要预后因素。虽然在毒理学和神经学条件下观察到 miRNA 的失调，但尚未对 miRNA 在纳米毒性中的作用进行机制研究。一类纳米材料包括碳纳米管（CNT），它是具有圆柱形纳米结构的碳的同素异形体。这些圆柱形结构具有新颖的特性，使其可用于纳米技术、电子、光学以及医学领域的许多应用。然而，它们的最终用途可能会受到潜在毒性的限制。在当前的应用中，我们假设暴露于 CNT 会导致神经元细胞中 miRNA 的失调，并对神经元功能产生负面影响。因此，两年期的具体目标是：1）确定体外碳纳米管暴露对神经元培养物的“直接”影响，以及体内呼吸碳纳米管暴露后对周围神经元再生的“间接”影响。 2) 表征神经元细胞中响应“直接”和“间接”CNT 暴露的 miRNA 表达特征。 3) 通过在体外和体内删除 Dicer 来研究 miRNA 耗尽是否会使神经元再生更容易受到 CNT 暴露的影响。本申请中的实验解决了碳纳米管神经毒性的临床重要问题。拟议的研究对于开发基于 miRNA 的方法来诊断、预后和治疗 CNT 相关健康风险至关重要。这项研究的长期目标是阐明 miRNA 在 CNT 神经毒性机制中的作用，为本科生和研究生提供研究机会，并提供用于建立未来 R01 资助申请的数据。公共卫生相关性：本申请中的实验解决了纳米颗粒神经毒性的表观遗传机制的临床重要问题。拟议的研究将增进我们对 microRNA 途径在介导纳米颗粒对神经系统的影响中的作用的理解，并将有助于为开发纳米颗粒相关健康问题的诊断、预后和治疗方法奠定基础。