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WC-Co nanoparticles in initiating angiogenesis by reactive oxygen species

WC-Co纳米颗粒通过活性氧引发血管生成

基本信息

批准号：
7851049
负责人：
BingHua Jiang
金额：
$ 40.74万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Nanoparticles are engineered structures with dimension of 100 nanometers or smaller. Available evidence indicates that the properties of nanoparticles may substantially differ from the same composition in the micrometer scale. However, the biological effects of nanoparticle exposure are little known yet. Our preliminary results show that exposure of epithelial cells to tungsten carbide cobalt (WC-Co) nanoparticles produced high levels of reactive oxygen species (ROS). WC-Co nanoparticles induced AKT and ERK1/2 activation, and increased the transcriptional activation of AP-1, NF-kappaB, and VEGF. We hypothesize that WC-Co nanoparticles induce angiogenesis through ROS signaling, which in turn regulates PI3K, AKT and ERK1/2 activities. To test this hypothesis, we will perform the following four aims. In Aim 1, we will identify which species of ROS are induced in lung epithelial cells exposed to the nanoparticls and the mechanism of ROS generation in the cells. Aim 2 will determine what signaling pathways and molecules are regulated by the nanoparticles, and whether they are mediated through ROS in the cells. Aim 3 will determine the effects of the nanoparticles in lung epithelial cells for inducing angiogenesis, and roles of ROS and signaling molecules in nanoparticle-inducing angiogenesis. Aim 4 will use mouse model and transgenic mice to further study the roles and mechanism of WC-Co nanoparticles in regulating signaling pathways and angiogenesis. This proposed work will provide the roles and mechanism of the nanoparticles in angiogenesis and other biological effects, and identify specific ROS-mediated signaling molecules for regulating angiogenesis. After we learn the biological responses of the nanoparticles and the underlined mechanism, we will be able to develop mechanism-based interventions, such as specific antioxidants, to decrease toxicity of WC-Co nanoparticles and other nanoparticles in the future. Nanoparticles are engineered structures with dimension of 100 nanometers or smaller. However, the biological effects of nanoparticle exposure are little known yet. In this study, we plan to study the biological effects of WC-Co nanoparticles by determining the roles and mechanism of the nanoparticles in inducing ROS production, PI3K, AKT, and ERK activation in human lung epithelial cells, and to study the effects of the nanoparticles in inducing angiogenesis. This proposed work will provide the roles and mechanism of the nanoparticles in inducing angiogenesis and other biological effects. This information is also useful for us to develop mechanism-based interventions, such as specific antioxidants, to decrease toxicity of WC-Co nanoparticles and other nanoparticles in the future.

描述(申请人提供)：纳米颗粒是尺寸在100纳米或更小的工程结构。现有证据表明，纳米颗粒的性质可能与微米级的相同成分有很大不同。然而，纳米颗粒暴露的生物学效应还鲜为人知。我们的初步结果表明，上皮细胞暴露在碳化钨钴纳米颗粒(WC-Co)中会产生高水平的活性氧(ROS)。WC-Co纳米颗粒可诱导AKT和ERK1/2的激活，并增强AP-1、NF-kappaB和VEGF的转录激活。我们推测WC-Co纳米颗粒通过ROS信号通路诱导血管生成，进而调节PI3K、AKT和ERK1/2的活性。为了验证这一假设，我们将实现以下四个目标。在目标1中，我们将确定暴露于纳米颗粒的肺上皮细胞中哪些种类的ROS被诱导，以及细胞中ROS的产生机制。目标2将确定纳米颗粒调节哪些信号通路和分子，以及它们是否通过细胞内的ROS介导。目的3将确定纳米颗粒在肺上皮细胞中诱导血管生成的作用，以及ROS和信号分子在纳米颗粒诱导血管生成中的作用。目的利用小鼠模型和转基因小鼠，进一步研究WC-Co纳米颗粒在调节信号通路和血管生成中的作用和机制。这项拟议的工作将提供纳米颗粒在血管生成和其他生物学效应中的作用和机制，并识别特定的ROS介导的信号分子来调节血管生成。在我们了解了纳米颗粒的生物反应和所强调的机制后，我们将能够开发基于机理的干预措施，例如特定的抗氧化剂，以降低WC-Co纳米颗粒和其他纳米颗粒的毒性。纳米粒子是尺寸为100纳米或更小的工程结构。然而，纳米颗粒暴露的生物学效应还鲜为人知。本研究拟通过研究WC-Co纳米颗粒在诱导人肺上皮细胞ROS生成、PI3K、AKT和ERK活化中的作用和机制，研究WC-Co纳米颗粒的生物学效应，并研究其诱导血管生成的作用。这项拟议的工作将提供纳米颗粒在诱导血管生成和其他生物效应方面的作用和机制。这些信息也有助于我们开发基于机制的干预措施，如特定的抗氧化剂，以降低未来WC-Co纳米颗粒和其他纳米颗粒的毒性。