Fate and effects of nanomaterials in the gastrointestinal tract

描述（由申请人提供）：纳米科学是一个令人兴奋和迅速发展的领域。工程纳米材料预计将用于许多不同的应用与不断增加的人类接触。在这些纳米材料中，碳纳米管（CNT）是富勒烯相关的石墨烯圆柱体，其表现出非常理想的特性，但也显示出潜在的危险特性。因此，认真调查潜在的不利健康影响是其安全和可持续发展的先决条件。肺部暴露于CNT导致氧化应激、炎症、肉芽肿形成和纤维化，这可能严重影响受影响个体的肺功能。已知纳米材料可激活Nlrp 3炎性体，导致IL-1？/IL-18释放和呼吸道急性炎症。Nlrp 3炎性体和IL-1？/IL-18在肠道免疫应答的调节中也起着关键作用。纳米材料暴露于呼吸道后的炎性体激活、炎症和疾病病理学已被联系起来;然而，有必要进一步研究以阐明CNT暴露对胃肠道（GI）的影响。该提议的目的是检验CNT暴露导致（1）由于Nlrp 3炎性体的活化和淋巴细胞的异常活化而导致的免疫应答失调，以及（2）对胃肠道中免疫介导的疾病的易感性改变的中心假设。我们将首次表征CNT在胃肠道内的毒性潜力，作为剂量、时间和暴露途径的函数，定义Nlrp 3炎性体在此过程中的作用，并确定肠道免疫组织的细胞反应（目的1）。我们还将使用TNBS诱导的结肠炎模型来确定CNT如何影响对IBD的易感性（目的2）。除了扩大我们对CNT如何影响免疫系统和胃肠道内疾病易感性的了解外，该研究计划还将通过生成关于暴露于CNT如何影响多个免疫相关终点的独特和高影响力信息来推进该领域。 公共卫生相关性：本提案的目的是确定CNT暴露对胃肠（GI）道的影响以及CNT诱导的炎性小体激活在急性和慢性肠易激疾病模型中的作用。这些研究可能有助于更好地理解肠道免疫调节所需的免疫细胞信号通路。

DESCRIPTION (provided by applicant): Nanoscience is an exciting and rapidly expanding field. Engineered nanomaterials are anticipated for use in many different applications with ever-increasing human exposure. Of these nanomaterials, carbon nanotubes (CNTs) are fullerene-related graphene cylinders that exhibit highly desirable properties, yet also display potentially hazardous traits. Therefore, a careful investigation into potential adverse health effects is a prerequisite for their safe and sustainable development. Pulmonary exposure to CNTs results in oxidative stress, inflammation, granuloma formation, and fibrosis, which may severely impact lung function in affected individuals. Nanomaterials are known to activate the Nlrp3 inflammasome resulting in IL-1¿/IL-18 release and acute inflammation in the respiratory tract. The Nlrp3 inflammasome and IL-1¿/IL-18 also play critical roles in the regulation of intestinal immune responses. Inflammasome activation, inflammation, and disease pathology following nanomaterial exposure in the respiratory tract have been connected; however, further research is necessary to clarify the impact of CNT exposure on the gastrointestinal (GI) tract. The goal of this proposal is to test the central hypothesis that CNT exposure results in (1) dysregulation of immune responses due to activation of the Nlrp3 inflammasome and aberrant activation of lymphocytes, and (2) altered susceptibility to immune-mediated diseases in the GI tract. We will perform the first characterization of CNTs' toxic potential within the GI tract as a function of dose, time, and route of exposure, define the role of the Nlrp3 inflammasome in this process, and determine the cellular response of the intestinal immune tissues (Aim 1). We will also determine how CNTs affect susceptibility to IBD using the TNBS-induced colitis model (Aim 2). In addition to expanding our knowledge of how CNTs affect the immune system and susceptibility to disease within the GI tract, this research program will advance the field by generating unique and high impact information regarding how exposure to CNTs affects multiple, immune-related endpoints in the context of animal models of common human diseases. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to determine the impact of CNT exposure on the gastrointestinal (GI) tract and the effects of CNT-induced inflammasome activation in acute and chronic models of irritable bowel disease. These studies may lead to a better understanding of immune cell signaling pathways required for immune regulation in the gut.