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）主要研究金属诱导的胃肠道免疫毒性机制