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Nanoneurotoxicity of Metal Oxide Nanomaterials and Neurodegeneration

金属氧化物纳米材料的纳米神经毒性和神经退行性变

基本信息

批准号：
9912082
负责人：
XUDONG HUANG
金额：
$ 38.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912082
关键词：
AD transgenic mice Address Air Pollution Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Apoptosis Biological Assay Blood - brain barrier anatomy Brain Cell Death Cerebrum Coupled Data Detection Disease model Encephalitis Energy Metabolism Engineering Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Exposure to Extravasation Fluorescence Microscopy Free Radicals Genetically Engineered Mouse Histologic Histology Image In Vitro Inflammation Inflammatory Response Inhalation Inhalation Exposure Knowledge Link Magnetic Resonance Imaging Measurement Memory Memory impairment Metabolic Metal exposure Methods Microfluidics Mission National Institute of Environmental Health Sciences National Institute of Neurological Disorders and Stroke Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuronal Dysfunction Outcome Oxidation-Reduction Oxidative Stress Parkinson Disease Pathogenesis Preventive measure Production Public Policy Regulation Research Research Personnel Risk Roentgen Rays Route Senile Plaques Stress Techniques Testing Tissues Trace Elements United States National Institutes of Health X ray microscopy absorption age related amyloid pathology animal data base biochip blood-brain barrier disruption blood-brain barrier permeabilization brain cell brain tissue cytokine epidemiologic data human disease imaging modality in vivo laser capture microdissection metabolic profile metal oxide microSPECT morris water maze mouse model nanomaterials nanoparticle nanoparticle exposure neuroinflammation neurotoxic neurotoxicity pandemic disease protein expression single photon emission computed tomography socioeconomics titanium dioxide

项目摘要

Project Summary/Abstract Growing evidence has indicated that exposure of nanoparticles such as MnO2, CuO, TiO2, etc., due to increasing use of these engineered nanomaterials (ENMs), induces nanoneurotoxicity that may pose risks for having neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), etc. However, the mechanisms of in vivo exposure and its potential contribution to neurodegeneration are not well known. Hence, our long-range objective is to study exposure of ENMs such as metal oxide nanoparticles and their nanoneurotoxicity and potential correlation to human diseases such as AD using both in vitro and in vivo disease models and imaging modalities. The specific hypothesis for this proposal is that exposure of CuO nanoparticles increases blood-brain barrier (BBB) permeability, enhances neurodegeneration, exacerbates cerebral Aβ amyloid pathology and associated neuroinflammation and redox stress, alter brain cytokine, biometal, and energy metabolic profiles. We base the hypothesis on previous observations and current key pilot data which suggest that: (i) long-term exposure to severe air pollution (highly possible exposure of metal oxide nanoparticles) is associated with neuroinflammation, BBB disruption, and Aβ1-42 accumulation (the salient neuropathological features of AD); (ii) CuO nanoparticle exposure increases BBB permeability via inhalation; (iii) exposure of CuO nanoparticles induce in vitro neurotoxicity, inflammation, and oxidative stress. To test our current hypothesis, we will (i) determine the effects of CuO nanoparticle inhalation on in vivo blood- brain barrier integrity and enhanced neurodegeneration; (ii) assess the effects of CuO nanoparticle inhalation on neuroinflammation, cerebral oxidative stress and Aβ amyloid pathology; (iii) evaluate the effects of CuO nanoparticle inhalation on memory function, biometal profiles in Aβ amyloid plaques and brain metabolic activities. We will use in vivo microSPECT (micro Single Photon Emission Computed Tomography) imaging and histology detection methods, cytokine microfluidic biochip assays, oxidative stress (4-HNE) and Aβ ELISA assays, high-energy X-ray fluorescence microscopy (µ-XRM) via the measurement of x-ray absorption spectra (µ-XAS) and x-ray absorption near edge spectra (µ-XANES) coupled with laser capture microdissection (LCM) tissue procuring technique, MRI/MRS, Morris Water Maze (MWM) memory test, and PS1/APP AD transgenic mouse model to achieve these experimental aims. Using our integrated experimental approaches, we believe that we will gain knowledge that can contribute to the making of public policy on regulating nanoparticle exposure and its neurotoxic effects upon the Central Nervous System (CNS), and further our understanding about potential risk of metal oxide nanoparticle exposure for neurodegeneration. More importantly, it will establish an experimental paradigm that will be very useful for investigating the nanoneurotoxicity and its potential contribution to etiopathogenesis of neurodegenerative diseases such as AD.

项目总结/摘要越来越多的证据表明，暴露于纳米颗粒如MnO 2、CuO、TiO 2等，由于越来越多地使用这些工程纳米材料（ENM），诱导纳米神经毒性，可能会对患有神经退行性疾病，如阿尔茨海默病（AD）、帕金森病（PD）等。然而，体内暴露的机制及其对神经退行性变的潜在贡献还不清楚知道的因此，我们的长期目标是研究ENM的暴露，如金属氧化物纳米颗粒和它们的纳米神经毒性和与人类疾病如AD的潜在相关性，疾病模型和成像模式。这一建议的具体假设是，纳米颗粒增加血脑屏障（BBB）的通透性，增强神经变性，加重神经功能障碍，脑Aβ淀粉样蛋白病理学和相关的神经炎症和氧化还原应激，改变脑细胞因子，生物金属和能量代谢谱我们根据以前的观察和当前的关键假设试验数据表明：（一）长期暴露于严重的空气污染（极有可能接触金属）氧化物纳米颗粒）与神经炎症、血脑屏障破坏和Aβ1-42蓄积相关（ AD的显著神经病理学特征）;（ii）CuO纳米颗粒暴露通过以下途径增加BBB通透性：吸入;（iii）暴露CuO纳米颗粒诱导体外神经毒性、炎症和氧化应激。为了检验我们目前的假设，我们将（i）确定CuO纳米颗粒吸入对体内血液的影响，脑屏障完整性和增强的神经变性;（ii）评估CuO纳米颗粒吸入的影响对神经炎症、脑氧化应激和Aβ淀粉样蛋白病理学的影响;（iii）评估CuO 纳米颗粒吸入对记忆功能、Aβ淀粉样蛋白斑块中的生物金属谱和脑代谢的影响活动我们将使用体内microSPECT（微型单光子发射计算机断层扫描）成像组织学检测方法、细胞因子微流控生物芯片检测、氧化应激（4-HNE）和Aβ ELISA检测通过测量X射线吸收光谱的高能X射线荧光显微镜（µ-XRM）（µ-XAS）和X射线吸收近边光谱（µ-XANES）结合激光捕获显微切割（LCM）组织获取技术、MRI/MRS、Morris水迷宫（MWM）记忆测试和PS1/APP AD转基因小鼠模型来实现这些实验目的。使用我们的综合实验方法，我们相信，我们将获得有助于制定有关管理纳米颗粒的公共政策的知识，暴露及其对中枢神经系统（CNS）的神经毒性作用，并进一步了解关于金属氧化物纳米颗粒暴露对神经变性的潜在风险。更重要的是会建立一个实验范式，这将是非常有用的研究纳米神经毒性及其对神经退行性疾病如AD的发病机制的潜在贡献。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

A hybrid machine learning-based method for classifying the Cushing's Syndrome with comorbid adrenocortical lesions.

一种基于混合机器学习的方法，用于将库欣综合症与合并症肾上腺皮质病变分类。

DOI：
10.1186/1471-2164-9-s1-s23
发表时间：
2008
期刊：
BMC GENOMICS
影响因子：
4.4
作者：
Yang, Jack Y.;Yang, Mary Qu;Luo, Zuojie;Ma, Yan;Li, Jianling;Deng, Youping;Huang, Xudong
通讯作者：
Huang, Xudong

Hyperbaric Oxygen Therapy for Alzheimer's Disease.

高压氧疗法治疗阿尔茨海默病。