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）：最近的观察结果表明，纳米材料可能对人体组织和细胞培养物有毒，从而导致氧化应激，炎性细胞因子产生和细胞死亡。虽然已知纳米级颗粒物的能力在呼吸系统中引起一系列问题，但最近的观察结果表明神经系统也可能很脆弱。特别是，表明纳米颗粒可以穿透影响与阿尔茨海默氏症和帕金森氏病有关的大脑信号传导的血脑屏障，并降低认知功能。但是，对神经系统的纳米材料毒性的机制进行了很少的研究。尚待解决的一个重要问题是，纳米颗粒如何触发神经细胞的变化，以及可以做些什么以尽早检测这些脱毛。最近的证据表明，microRNA（miRNA）是调节基因表达的小型非编码RNA，可能是由环境暴露引起的神经变性的重要预后因素。虽然在毒理学和神经系统条件下观察到了miRNA的失调，但尚未就miRNA在纳米毒性中的作用进行机械研究。一类纳米材料包括碳纳米管（CNT），它们是带有圆柱纳米结构的碳的同异形。这些圆柱结构具有新颖的特性，使其在纳米技术，电子，光学以及医学中的许多应用中有用。但是，它们的最终用法可能受到潜在毒性的限制。在当前应用中，我们假设暴露于CNT会导致神经元细胞中miRNA的失调，并会对神经元功能产生负面影响。因此，在两年期间的具体目的是：1）确定“直接” CNTS暴露于体外神经元培养物的影响，并在体外对周围神经元再生的影响“间接”影响。 2）表征神经元细胞中的miRNA表达特征，以响应“直接”和“间接” CNTS暴露。 3）研究miRNA耗竭是否会使神经元再生通过在体外和体内删除DICER来更容易受到CNT的暴露。该应用程序中的实验解决了CNTS神经毒性的临床重要问题。拟议的研究对于为开发基于miRNA的方法来诊断，预后和治疗与CNTS相关的健康风险的方法至关重要。这项调查的长期目标是阐明miRNA在CNT神经毒性的基础机制中的作用，为本科生和研究生提供研究机会，并提供有关建立未来R01赠款应用程序的数据。公共卫生相关性：该申请中的实验涉及纳米颗粒神经毒性表观遗传机制的临床重要问题。拟议的研究将促进我们对MicroRNA途径在介导纳米颗粒对神经系统的作用中的作用的理解，并将有助于建立开发纳米粒子相关健康问题的诊断，预后和治疗方法的基础。