WC-Co nanoparticles in initiating angiogenesis by reactive oxygen species

描述（由申请人提供）：纳米颗粒是尺寸为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尺度上的相同成分有很大不同。然而，纳米颗粒暴露的生物学效应知之甚少。我们的初步结果表明，暴露于碳化钨钴（WC-Co）纳米粒子的上皮细胞产生高水平的活性氧（ROS）。WC-Co纳米颗粒诱导AKT和ERK 1/2活化，并增加AP-1、NF-κ B和VEGF的转录活化。我们假设WC-Co纳米颗粒通过ROS信号传导诱导血管生成，ROS信号传导反过来调节PI 3 K、AKT和ERK 1/2活性。为了验证这个假设，我们将执行以下四个目标。在目标1中，我们将确定在暴露于纳米颗粒的肺上皮细胞中诱导哪种ROS以及细胞中ROS产生的机制。目标2将确定纳米颗粒调节的信号通路和分子，以及它们是否通过细胞中的ROS介导。目的3：研究纳米颗粒对肺上皮细胞的促血管生成作用，以及活性氧和信号分子在纳米颗粒促血管生成中的作用。目的4利用小鼠模型和转基因小鼠进一步研究WC-Co纳米颗粒在调控信号通路和血管生成中的作用和机制。本研究将为纳米粒子在血管生成和其他生物学效应中的作用和机制提供理论依据，并确定特定的ROS介导的信号分子来调节血管生成。在我们了解纳米颗粒的生物反应和强调的机制之后，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WC-Co纳米颗粒和其他纳米颗粒的毒性。纳米颗粒是尺寸为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知之甚少。在这项研究中，我们计划通过确定纳米颗粒诱导人肺上皮细胞产生ROS，PI 3 K，AKT和ERK激活的作用和机制来研究WC-Co纳米颗粒的生物学效应，并研究纳米颗粒诱导血管生成的作用。本研究将为纳米粒子在诱导血管生成等生物学效应中的作用和机制提供理论依据。这些信息也有助于我们开发基于机制的干预措施，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。

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.