MicroRNA pathway in mechanisms of nanoparticles neurotoxicity

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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.