Mechanisms of Modulation of Gut Immunity by Ingested Uranium and Mixed Metal Exposures

摄入铀和混合金属暴露调节肠道免疫的机制

• 批准号: 10707527
• 负责人: Eliseo F Castillo
• 金额: $ 27.77万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707527
• 关键词: Address; Affect; Albumins; Animals; Aromatic Hydrocarbons; Arsenic; Autoimmune Diseases; Biological; Biological Markers; Blood; Cell Line; Cell surface; Cells; Chronic; Citrates; Collaborations; Colon; Communities; Data; Disease; Electrical Resistance; Elements; Environment; Epithelial Cells; Epithelium; Exposure to; Feces; Functional disorder; Funding; Gastrointestinal tract structure; Goals; Health; Human; Immune; Immune System Diseases; Immunity; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Ingestion; Inhalation; Intestinal permeability; Intestines; Intraepithelial T-Lymphocyte; Investigation; Lactoferrin; Lamina Propria; Large Intestine; Leukocyte L1 Antigen Complex; Ligands; Lung; Lymphocyte; Lymphocyte Subset; Lymphoid Cell; MRL/MpJ Mouse; Membrane; Messenger RNA; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolism; Metagenomics; Metal exposure; Metals; Modeling; Mus; New Mexico; Oral; Oral Ingestion; Organoids; Orthovanadate; Oxidative Stress; Oxides; Participant; Particulate; Pathway interactions; Permeability; Phase; Pilot Projects; Predisposition; Production; Proteins; Research; Sampling; Sampling Studies; Series; Signal Recognition Particle; Site; Small Intestines; Sodium; Superfund; T-Lymphocyte; Testing; Tight Junctions; Tissues; Toxic effect; Universities; Uranium; Vanadium; Work; absorption; biomarker signature; community living; cytokine; drinking water; dysbiosis; exposure route; fecal microbiome; gastrointestinal; gut microbiome; gut microbiota; hard metal; immune function; immunoregulation; immunotoxicity; in vivo; inflammatory marker; intestinal epithelium; intraepithelial; mRNA Expression; member; metabolome; metabolomics; metagenomic sequencing; metal poisoning; microbiome; microbiota; mitochondrial metabolism; nanomaterials; novel; programs; protein expression; receptor; remediation; stool sample; toxic metal; translational study; tribal lands; uranyl acetate; wound healing

BioProject- Gut (BP Gut) focuses on mechanisms of metal-induced immunotoxicity in the gastrointestinal tract (GIT) of mice and humans in a series of studies using mouse and human cells and tissues. BP Gut is highly integrated with all SRP METALS environmental and biologic projects, including BP Lung and BP Comm. BP Gut relies on the work of the CEC and the DMAC. An overall theme of the studies is the understanding of how metals present in or near mine sites in New Mexico might expose community members leading to immunotoxicity. We focus on soluble and particulate forms uranium (U), and vanadium (V) given via oral routes of exposure, because multiple exposures to these types of mixed metals has been observed in our community partners. We have previously shown during Phase 1 that oral (45d) drinking water exposure of mice to U leads to high exposures of GIT leading to significant changes in lymphoid and epithelial cells in the small and large intestines. In SA1, mouse studies will explore in vivo, ex vivo, and in vitro studies following exposures to uranyl acetate (UA, soluble) and uranium citrate (UCit, insoluble nanomaterial), sodium orthovanadate (Na3VO4, soluble) and vanadium oxide (V2O4, insoluble). These metals will be explored alone and in combination with other metals, including arsenic. Environmentally derived mine samples rich in carnotite will also be studied in mice. We will screen for mRNA changes in small and large intestinal snips focusing on cytokines, oxidative stress, and aromatic hydrocarbon receptor (AhR) pathways. An additional novel aspect of these studies is that we will perform microbiome metagenomic analyses on the feces obtained from these mice, and we will screen the feces using a large metabolomic panel to determine possible pathways responsible for immune modulation. In SA2, we will examine the toxicity of these same metals and mixtures on human colonic organoids obtained from normal human donors. We will assess metabolic changes in these tissues following in vitro exposures and we will assess changes in epithelial barrier function using both organoids and human colonic cell lines. Changes in transepithelial electrical resistances, mRNA and protein expression for membrane tight junction molecules will be studied to understand mechanisms of barrier disruption. In SA3, working with the CEC and BP Comm, we will examine stool samples from study participants in the community for metal exposure, changes in inflammatory biomarkers, microbiome metagenomics, and metabolomic profiles examined in SA1 and SA2. These studies will rely on statistical and mixed metal analyses developed by DMAC. The ultimate goal of these studies is to address community concerns regarding exposure to mixed metals from abandoned uranium mines and other hard metal mines leading to potential immunologic changes and diseases. Data from these studies will inform communities through CEC on how to avoid exposures and inform environmental projects (ESE PM, ESE Remed) on potential remediation of these sites.

Bioproject- ut（BP肠道）重点介绍胃肠道中金属诱导的免疫毒性的机制 在一系列使用小鼠，人类细胞和组织的研究中，小鼠和人类的（GIT）。 BP肠道高度 与所有SRP金属环境和生物学项目集成，包括BP肺和BP COMM。 bp 肠道依靠CEC和DMAC的工作。研究的总体主题是了解如何 在新墨西哥州矿场内或附近存在的金属可能会暴露于社区成员 免疫毒性。我们专注于可溶性和颗粒形式的铀（U），以及通过口腔路线给出的钒（V） 暴露于暴露，因为在我们的社区中观察到了这些类型的混合金属的多种暴露 合作伙伴。我们以前在第1阶段表明，口服（45D）小鼠饮用水暴露于U导线 高暴露于GIT，导​​致大小 肠。在SA1中，小鼠研究将在体内，体内和体外研究探索，并在暴露于铀酰上 在 可溶性）和氧化钒（V2O4，不溶性）。这些金属将单独探索并结合 其他金属，包括砷。环境衍生的矿物样品也将在 老鼠。我们将筛选出针对细胞因子的大小肠刺激的mRNA变化，氧化 应力和芳族烃受体（AHR）途径。这些研究的另一个新颖方面是 我们将对从这些小鼠获得的粪便进行微生物组宏基因组分析，我们将筛选 使用大型代谢组面的粪便来确定可能导致免疫的途径 调制。在SA2中，我们将检查这些相同金属和混合物对人类结肠的毒性 从正常人类供体获得的类器官。我们将评估这些组织中这些组织中的代谢变化 体外暴露，我们将使用类器官和人类评估上皮屏障功能的变化 结肠细胞系。旋转电阻的变化，mRNA和蛋白质表达的变化 将研究膜紧密连接分子，以了解屏障破坏的机制。在SA3中 与CEC和BP通信合作，我们将检查社区研究参与者的粪便样本 对于金属暴露，炎症生物标志物，微生物组宏基因组学和代谢组谱的变化 在SA1和SA2中检查。这些研究将依赖于由统计和混合金属分析。 DMAC。这些研究的最终目的是解决社区对接触混合的关注 来自废弃铀矿和其他硬金属矿的金属导致潜在的免疫学变化 和疾病。来自这些研究的数据将通过CEC告知社区如何避免暴露和 向环境项目（ESE PM，ESE恢复）提供信息，以解决这些站点的潜在修复。