Modulation of Immune-GI Function by NanoAg

研究计划 A.具体目标。 项目2的目的是通过将模型生物体，特别是小鼠暴露在含有银、金或硅酸盐的纳米材料中，产生生理和病理生物学相关的数据。这些基本信息是开发这些纳米材料风险分析的基础，将在项目3中开发。此外，它还将为项目1和科学核心中产生的材料科学和体外机械数据提供生理学相关性的原材料和基准。将评估纳米材料质量比和剂量以及宿主和环境因素的变化，特别是性别和肠道微生物状况。科学目标和功能将使用多分散的纳米银和纳米Au来实现，这些纳米银和纳米Au的平均直径为100 nm，来自商业(真实世界)来源，以及来自项目1的表征良好的非晶态SiO{2}球(平均直径为15，80和100 nm)混合在一起，给出关于颗粒数量的模拟正态分布。在实验的一部分中，一组小鼠将在饮用水中注射抗生素头孢哌酮(0.5 mg/ml)，因为它已经被证明改变了人类[1，2]和小鼠[3，4]的肠道微生物群的数量和组成。这种实验方法将被用来检验这样一个假设，即工程纳米材料改变了肠道微生物群的组成，并损害了肠道上皮屏障的“色调”(项目1和2之间的合作)。进一步假设，抗生素诱导的微花组成和数量的改变将增加工程纳米材料的吸收，并在肠道上皮相关淋巴组织、肝和脾诱导促炎状态。这些假设将通过以下具体目标加以解决： 具体目标1：使用具有良好特性的多分散制剂(Science Core)，在正常状态和微生物改变(抗生素治疗)状态(与项目1协调)下，确定所有三种材料的药代动力学曲线作为剂量和时间的函数 具体目标2：确定目标1中详述的所有三种材料在正常和微生物改变状态下的组织分布作为剂量和时间的函数 具体目标3：确定所有三种材料在正常和微生物改变状态下的毒理学病理学特征 具体目标4：确定肠道、血液和主要淋巴器官中所有三种物质在正常和微生物改变状态下的免疫学特征

RESEARCH PLAN A. SPECIFIC AIMS. The intent of project 2 is to generate physiologically and pathobiologically relevant data via the exposure of a model organism, specifically the mouse, to nanomaterials containing silver, gold, or silicate. This basic information is fundamental to the development of risk analyses for these nanomaterials, as will be developed in Project 3. Additionally, it will provide raw materials and benchmarks of physiologic relevance for the materials science and in vitro mechanistic data generated in Project 1 and the Scientific Core. Variations in nanomaterial mass ratios and dose as well as host and environmental factors, specifically sex and gut microbial status, will be evaluated. The Scientific Aims and Functions will be achieved using polydisperse nanoAg and nanoAu with a mean diameter <100 nm obtained from commercial ('real world) sources and well characterized amorphous SiO{2} spheres from Project 1 (15, 80 and 100 nm mean diameter) mixed to give a simulated normal distribution with respect to particle number. A subset of mice will be administered the antibiotic cefoperazone (0.5 mg/ml) in drinking water for a portion of the experiment as it has been demonstrated to alter the number and composition of intestinal microbiota in humans [1, 2] and mice [3,4]. This experimental approach will be used to test the hypothesis that engineered nanomaterials alter the composition of enteric microflora and compromise the 'tone' of the epithelial barrier in the gut (collaboration between Projects 1&2). It is further hypothesized that antibiotic-induced alterations in microfloral composition and number will increase absorption of engineered nanomaterials and induce a pro-inflammatory state in the gut epithelium associated lymphoid tissues, liver and spleen. These hypotheses will be addressed by the following specific aims: Specific aim 1: Determine pharmacokinetic profiles as a function of dose and time for all three materials in a normal and a microbiotically altered (antibiotic treated) state (coordinated with Project 1) using well-characterized polydisperse preparations (Scientific Core) Specific aim 2: Determine tissue distributions as a function of dose and time for all three materials detailed in Aim 1 in a normal and a microbially altered state Specific aim 3: Determine the toxicologic pathology profile for all three materials in a normal and a microbiotically altered state Specific aim 4: Determine the immunologic profile for all three materials in the gut, blood and major lymphoid organs in the normal and microbiotically altered state