Modulation of Immune-GI Function by NanoAg

研究计划 A.具体目标。 项目2的目的是通过将模式生物（特别是小鼠）暴露于含银、金或硅酸盐的纳米材料，生成生理学和病理学相关数据。这些基本信息对于开展这些纳米材料的风险分析至关重要，项目3将开展这些分析。此外，它将为项目1和科学核心中生成的材料科学和体外机械数据提供与生理相关的原材料和基准。将评价纳米材料质量比和剂量的变化以及宿主和环境因素，特别是性别和肠道微生物状态。科学目的和功能将使用从商业（“真实世界”）来源获得的平均直径<100 nm的多分散纳米Ag和纳米Au以及从项目1获得的充分表征的无定形SiO{2}球（15、80和100 nm平均直径）来实现，混合以给出相对于颗粒数的模拟正态分布。在实验的一部分中，将对一部分小鼠给予含抗生素头孢哌酮（0.5 mg/ml）的饮用水，因为已证明其可改变人类[1，2]和小鼠[3，4]肠道微生物群的数量和组成。这种实验方法将用于测试工程纳米材料改变肠道微生物菌群组成并损害肠道上皮屏障的“色调”的假设（项目1和2之间的合作）。进一步假设，抗生素诱导的微菌群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、肝脏和脾脏中诱导促炎状态。这些假设将通过以下具体目标加以解决： 具体目标1：使用充分表征的多分散制剂（Scientific Core），确定所有三种材料在正常和微生物改变（抗生素处理）状态下（与项目1协调）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与剂量和时间的函数关系 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：确定正常和微生物改变状态下所有三种材料在肠道、血液和主要淋巴器官中的免疫学特征

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