Causal Molecular Mechanisms Linking Drinking Water Metal Exposures to Cardiometabolic Disease

饮用水金属暴露与心脏代谢疾病之间的因果分子机制

• 批准号: 10707911
• 负责人: Brandon L Pearson
• 金额: $ 26.18万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707911
• 关键词: Adult Children; Affect; Alleles; Animal Model; Apolipoprotein E; Arsenic; Atherosclerosis; Behavioral; Biological Markers; Biological Models; Blood; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Chemicals; Chronic; Chronic Disease; Clinical; Collaborations; Communities; Consumption; DNA Methylation; Data; Development; Developmental Toxicant; Diabetes Mellitus; Dietary Factors; Dietary Intervention; Elements; Environment; Epidemiology; Epigenetic Process; Experimental Animal Model; Exposure to; Folic Acid; Future; Gene Expression; Genetically Engineered Mouse; Half-Life; Health; Heart; Histologic; Human; Hypertension; Immunologics; Individual; Inflammation; Intervention; Knowledge; Laboratory mice; Life; Link; Liver; Mediator; Metabolic; Metabolism; Metal exposure; Metals; Methylation; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Mus; Native Americans; Obesity; Observational Study; Organ; Outcome; Pancreas; Participant; Pathogenicity; Pathology; Pathway interactions; Persons; Physiological; Population; Predisposition; Relative Risks; Research; Research Project Grants; Resources; Risk; Role; Sampling; Science; Signal Recognition Particle; Site; South Dakota; Superfund; System; Testing; Therapeutic Intervention; Tissues; Toxic effect; Toxicology; Transgenic Mice; Tribes; Universities; Uranium; Urine; Water; animal tissue; biobank; body system; burden of illness; cardiometabolism; cell type; cohort; community engagement; contaminated drinking water; data modeling; diabetes risk; dietary; disease phenotype; drinking water; early life exposure; efficacy evaluation; folic acid supplementation; gene function; ground water; humanized mouse; improved; insight; intergenerational; lifestyle factors; metabolome; metabolomics; molecular marker; mouse model; multiple omics; mutant; novel; prevent; preventive intervention; programs; response; screening; superfund site; therapeutic evaluation; tool; transcriptomics; urinary; water sampling; waterborne; well water

Project 4 Summary Chronic exposure to metals and metalloids (hereafter metals) is detrimental to human cardiovascular and metabolic health. Native Americans living in the Northern Plains consume well water with elevated levels of arsenic (As) and uranium (U), common Superfund site contaminants. Metal exposures in these populations are epidemiologically linked to high rates of cardiovascular disease and diabetes. However, strategies to prevent or treat the disease burdens related to groundwater metal exposures have been limited by poor understanding of the molecular mechanisms of individual and combined metal exposures. To fill this gap, Project 4 of the Columbia University Northern Plains Superfund Research Program (CUNP-SRP) will establish human-relevant mouse models of chronic metal exposures and cardiometabolic disease to comprehensively evaluate such mechanisms. We will leverage genetically engineered mouse models to investigate developmental vulnerability, tissue and cellular level effects, and specific molecular mediators of exposure–outcome relationships. We will expose mice to environmentally relevant concentrations of As and/or U in addition to well water samples containing a naturally elevated As/U mixture that people in the Northern Plains consume (collected in Project 1). We will then determine the cardiometabolic effects of these exposures, compare early-life to lifelong exposures, and determine how dietary folate mitigates As toxicity. Aim 1 will define health impacts and developmental vulnerability of early-life or lifelong exposure to As/U in drinking water in genetically engineered mice. Mouse cardiometabolic health will be evaluated longitudinally with a battery of clinical, histological, behavioral, and functional tests with a focus on atherosclerosis, hypertension, adiposity and diabetes, in the context of a hyperlipidemic model. Moreover, this aim will generate a biobank of As and/or U exposed animal tissues for future studies, creating an expansive resource for collaborative research projects with other SRP centers. Aim 2 will profile mouse multi-omics biomarkers altered by early-life or lifelong exposure to As/U in drinking water. DNA methylation, gene expression, and the metabolome will be profiled in mouse blood, liver, and pancreas samples collected in Aim 1 to reveal molecular markers of metal exposure and cardiometabolic disease. Molecular signatures in mice will be compared to Project 3 human molecular signatures to identify conserved pathogenic mechanisms as well as the utility of blood biospecimen markers to represent target organ pathologies not typically available in human observational research. Aim 3 will evaluate the human-relevant potential for and mechanisms of dietary folate supplementation to reduce As toxicity. Since laboratory mice rapidly eliminate consumed As via methylation, we will use mice that instead metabolize As similarly to humans. Through these three aims, we will establish a valid animal model system for causal discovery science and to test therapeutic interventions to tackle the extensive and disproportionate disease burden attributable to groundwater metal exposures affecting tribal populations in the Northern Plains.

项目4摘要 长期暴露于金属和金属（以下金属）对人的心血管有害 代谢健康。居住在北部平原的美洲原住民消耗井水，水平升高 砷（AS）和铀（U），普通超级基金部位污染物。这些人群中的金属暴露是 流行病学与心血管疾病和糖尿病的高率有关。但是，预防或 治疗与地下水金属暴露有关的疾病伯恩一家受到对 单个金属暴露的分子机制。为了填补这一空白，哥伦比亚项目4 大学北部平原超级基金研究计划（CUNP-SRP）将建立与人相关的鼠标 慢性金属暴露和心脏代谢疾病的模型，以全面评估这种机制。 我们将利用基因工程的小鼠模型来研究发育脆弱性，组织和 细胞水平效应以及暴露与outcome关系的特定分子介体。我们将暴露老鼠 除了含有自然的水样品外，还可以与环境相关的AS和/或U 升高的AS/U混合物在北部平原上消耗的混合物（在项目1中收集）。然后我们将确定 这些暴露的心脏代谢作用，将早期生活与终身暴露相比，并确定如何 饮食叶酸会减轻毒性。 AIM 1将定义健康的影响和发展脆弱性 在基因工程小鼠的饮用水中，早期生命或终身暴露于AS/U。老鼠 心脏代谢健康将通过一系列临床，组织学，行为和 功能测试的重点是动脉粥样硬化，高血压，肥胖和糖尿病 高脂学模型。此外，此目标将产生AS和/或U暴露的动物组织的生物库 未来的研究，为与其他SRP中心的协作研究项目创造了额外的资源。目的 2将介绍鼠标多矩生物标志物，随着早期或终身暴露于As/U的饮酒而改变 水。 DNA甲基化，基因表达和代谢组将在小鼠血液，肝脏和 AIM 1收集的胰腺样品揭示了金属暴露和心脏代谢的分子标记 疾病。将小鼠的分子特征与项目3人类分子特征进行比较，以鉴定 保守的致病机制以及血液生物测量标记的效用以表示目标器官 人类观察研究中通常不可用的病理。 AIM 3将评估与人类相关的 饮食中补充叶酸的潜力和机制可降低毒性。自实验室以来 小鼠通过甲基化迅速消除了消耗的小鼠，我们将使用与代谢相似的小鼠 人类。通过这三个目标，我们将建立一个有效的因果发现科学动物模型系统 并测试治疗性干预措施，以应对伯恩的广泛而不成比例的疾病 地下水金属暴露影响北部平原部落人口。