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（由申请人提供）：纳米颗粒是工程结构，尺寸为100纳米或更小。可用的证据表明，纳米颗粒的性质可能与千分尺尺度上的同一组成有很大不同。但是，纳米颗粒暴露的生物学作用尚不清楚。我们的初步结果表明，上皮细胞暴露于钨碳化钴（WC-CO）纳米颗粒会产生高水平的活性氧（ROS）。 WC-CO纳米颗粒诱导AKT和ERK1/2激活，并增加了AP-1，NF-KAPPAB和VEGF的转录激活。我们假设WC-CO纳米颗粒通过ROS信号传导诱导血管生成，进而调节PI3K，AKT和ERK1/2活性。为了检验这一假设，我们将执行以下四个目标。在AIM 1中，我们将确定在暴露于纳米骨骼的肺上皮细胞中诱导了哪些ROS物种以及细胞中ROS产生的机理。 AIM 2将确定哪些信号通路和分子受纳米颗粒的调节，以及它们是否通过细胞中的ROS介导。 AIM 3将确定纳米颗粒在肺上皮细胞中对诱导血管生成的影响，以及ROS和信号分子在纳米颗粒诱导的血管生成中的作用。 AIM 4将使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。这项提出的工作将提供纳米颗粒在血管生成和其他生物学作用中的作用和机制，并确定特定的ROS介导的信号分子来调节血管生成。在了解纳米颗粒的生物学反应和带下划线的机制后，我们将能够开发基于机制的干预措施，例如特定的抗氧化剂，以降低未来WC-CO纳米颗粒和其他纳米颗粒的毒性。纳米颗粒是工程结构，尺寸为100纳米或更小。但是，纳米颗粒暴露的生物学作用尚不清楚。在这项研究中，我们计划通过确定纳米颗粒在诱导人肺上皮细胞中诱导ROS产生，PI3K，AKT和ERK激活中的作用和机制来研究WC-CO纳米颗粒的生物学作用，并研究纳米颗粒在诱导血管生成中的作用。这项提出的工作将提供纳米颗粒在诱导血管生成和其他生物学作用中的作用和机制。对于我们来说，开发基于机制的干预措施（例如特定抗氧化剂）以降低WC-CO纳米颗粒和其他纳米颗粒的毒性，也很有用。