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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(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产生毒性，导致氧化应激、炎性细胞因子产生和细胞死亡。虽然已知纳米颗粒物质的能力会导致呼吸系统的一系列问题，但最近的观察表明，神经系统可能也很脆弱。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症有关的大脑信号，并降低认知功能。然而，纳米材料对神经系统的毒性机制尚未得到很好的研究。一个有待解决的重要问题是，纳米颗粒如何引发神经细胞的变化，以及可以做些什么来及早发现这些缺陷。最近的证据表明，microRNAs(MiRNAs)，一种调节基因表达的非编码小RNA，可能是环境暴露引起的神经退行性变的一个重要预后因素。虽然在毒理学和神经学条件下已经观察到miRNAs的调节失调，但还没有关于miRNAs在纳米毒性中的作用的机制研究。纳米材料的一类包括碳纳米管(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，使其在纳米技术、电子学、光学以及医学等领域的许多应用中都很有用。然而，它们的最终使用可能会受到其潜在毒性的限制。在目前的应用中，我们假设暴露于碳纳米管将导致神经细胞中miRNAs的调节失调，并将对神经元功能产生负面影响。因此，这两年的具体目标是：1)确定“直接”接触碳纳米管对体外培养的神经元的影响，以及“间接”接触体内呼吸性碳纳米管对周围神经元再生的影响。2)表征神经细胞对“直接”和“间接”碳纳米管暴露的miRNA表达特征。3)通过在体内和体外研究缺失miRNAs是否会使神经元再生更容易受到CNT的影响。这一应用中的实验解决了碳纳米管神经毒性的临床重要问题。拟议的研究将为开发基于miRNA的方法诊断、预测和治疗碳纳米管相关的健康风险奠定基础。这项研究的长期目标是阐明miRNAs在CNTs神经毒性潜在机制中的作用，为本科生和研究生提供研究机会，并为未来R01拨款申请提供数据。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这一临床重要问题。这项研究将促进我们对microRNA途径在纳米颗粒对神经系统的调节作用中的作用的理解，并将有助于为纳米颗粒相关健康问题的诊断、预后和治疗方法的发展奠定基础。