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-Gut (BP Gut) 专注于金属诱导的胃肠道免疫毒性机制 使用小鼠和人类细胞和组织进行的一系列研究中，对小鼠和人类进行了胃肠道（GIT）研究。 BP 肠道高度 与所有 SRP METALS 环境和生物项目集成，包括 BP Lung 和 BP Comm。血压 Gut 依赖于 CEC 和 DMAC 的工作。研究的总体主题是了解如何 新墨西哥州矿场内或附近存在的金属可能会暴露社区成员，导致 免疫毒性。我们专注于通过口服途径给予的可溶性和颗粒形式的铀 (U) 和钒 (V) 暴露，因为在我们的社区中观察到多次暴露于这些类型的混合金属 合作伙伴。我们之前在第 1 阶段已证明，小鼠口服（45 天）饮用水暴露于 U 铅 胃肠道的高暴露导致小和大的淋巴和上皮细胞的显着变化 肠子。在 SA1 中，小鼠研究将探索暴露于铀酰后的体内、离体和体外研究 醋酸盐（UA，可溶）和柠檬酸铀（UCit，不溶性纳米材料）、原钒酸钠（Na3VO4， 可溶）和氧化钒（V2O4，不溶）。这些金属将单独或与其他金属结合探索 其他金属，包括砷。富含卡诺石的环境衍生矿山样品也将在 老鼠。我们将筛选小肠和大肠剪中的 mRNA 变化，重点关注细胞因子、氧化 压力和芳香烃受体（AhR）途径。这些研究的另一个新颖之处是 我们将对这些小鼠的粪便进行微生物组宏基因组分析，并筛选 使用大型代谢组学面板来确定粪便中负责免疫的可能途径 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 从正常人类捐赠者获得的类器官。我们将评估这些组织的代谢变化 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。跨上皮电阻、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， 我们将与 CEC 和 BP Comm 合作，检查社区研究参与者的粪便样本 对于金属暴露、炎症生物标志物的变化、微生物组宏基因组学和代谢组学概况 在 SA1 和 SA2 中进行了检查。这些研究将依赖于统计和混合金属分析 DMAC。这些研究的最终目标是解决社区对接触混合环境的担忧 来自废弃铀矿和其他硬金属矿的金属导致潜在的免疫变化 和疾病。这些研究的数据将通过 CEC 告知社区如何避免接触和 向环境项目（ESE PM、ESE Remed）通报这些场地的潜在修复情况。