The UNC Chapel Hill Superfund Research Program (UNC-SRP)

北卡罗来纳大学教堂山超级基金研究计划 (UNC-SRP)

基本信息

批准号：
10207906
负责人：
Rebecca Fry
金额：
$ 46.43万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207906
关键词：
2019-nCoV Address Affect Antiviral Agents Arsenic Biomedical Research COVID-19 COVID-19 pandemic Carcinogens Cardiovascular system Cells Chronic County Development Disease Disease Outcome Emergency Situation Environmental Exposure Epithelial Cells Exposure to Female Functional disorder Gene Expression Genetic Genetically Engineered Mouse Genotype Germ Cells Goals High Prevalence Host Defense Human Hypertension Immune Immune System Diseases Immune response Immunosuppressive Agents Impairment Individual Infection Influenza Laboratories Metabolism Metal exposure Methyltransferase Modeling Molecular Profiling Mouse Strains Mus Nasal Epithelium Natural Immunity Neurotoxins Non obese Non-Insulin-Dependent Diabetes Mellitus North Carolina Obesity Organ Outcome Pathogenesis Pathologic Pathology Peptidyl-Dipeptidase A Phenotype Physiological Poison Predisposition Privatization Pulmonary Pathology Registries Research Research Project Grants Respiratory Tract Infections Risk Role Serine Protease Severe Acute Respiratory Syndrome Severities Superfund System TMPRSS2 gene Testing Universities Viral Virus Replication airway epithelium base biological sex comorbidity contaminated drinking water contaminated water coronavirus disease design diabetic diabetogen disease registry drinking water human model in vitro Model infection risk male mortality mouse model novel oxidation pandemic disease pathogen pollutant programs public health relevance respiratory response sex toxicant

项目摘要

ABSTRACT This proposal is being submitted as an Emergency Competitive Revision for the University of North Carolina (UNC) Superfund Research Program (SRP) in the context of the Coronavirus Disease 2019 (COVID-19) pandemic. We focus on inorganic arsenic (iAs), the #1 contaminant of the Agency for Toxic Substances Registry (ATSDR) contaminating drinking water around the globe. iAs is toxic to many organs in the body, acting as a carcinogen, diabetogen, neurotoxicant, and immunosuppressant. Notably, in several of the North Carolina counties where iAs levels in drinking water are high, the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is also high, indicating that a co-exposure to iAs and SARS-CoV-2 likely occurs. This co-exposure to iAs on the susceptibility to SARS-CoV-2 infection and COVID-19 severity has never been studied. The goal of this proposal is to characterize the interaction between iAs exposure and SARS-CoV- 2 infection using differentiated primary human nasal epithelial cells, an established in vitro model for respiratory infections, and a novel humanized hAS3MT mouse strain, in which the metabolism of iAs and disposition of its metabolites resemble those in humans. In a strong, transdisciplinary approach, we will use differentiated primary human nasal epithelial cells and a humanized hAS3MT mice to test the hypothesis that chronic exposure to iAs enhances susceptibility to SARS-CoV2 infection and severity of COVID-19. While integrating human and mouse models, we will also examine the role of sex and genetic background on the disease outcome. The two new additional Aims include: (Aim 1) Identify the effects of iAs and its metabolites on SARS-CoV-2 infection in differentiated primary human nasal epithelial cells; and (Aim 2) Characterize the effects of iAs exposure on SARS-CoV-2 MA infection and COVID-19 outcomes in hAS3MT mice. In Aim 1, we test the hypothesis is that exposure to iAs or its metabolites enhances susceptibility to and severity of SARS-CoV-2 infection in the human nasal epithelial cells. In Aim 2, we will compare immune response, viral titer, lung pathology and mortality in hAS3MT mice exposed to iAs in drinking water (0, 40, or 400 ppb) and infected with a mouse-adapted SARS-CoV-2 that has been recently created at UNC Chapel Hill. To assess the role of sex and genetics, we will use male and female hAS3MT mice with C57BL/6NCrl and 129S6/SvEvTac backgrounds. The proposed research utilizes novel laboratory models that are available only at UNC and are uniquely suited for studies of the interaction between environmental iAs exposure and SARS-CoV2 infection. The proposed research addresses a critical need for understanding of the interaction between a widespread environmental exposure and a pandemic infection that affects hundreds of millions of people worldwide.

抽象的该提案作为北卡罗来纳大学的紧急竞争性修订提交 (UNC) 2019 年冠状病毒病 (COVID-19) 背景下的超级基金研究计划 (SRP) 大流行。我们专注于无机砷 (iAs)，它是有毒物质登记局排名第一的污染物 (ATSDR) 污染了全球的饮用水。 iAs 对体内许多器官有毒，致癌物、糖尿病原、神经毒物和免疫抑制剂。值得注意的是，在北卡罗来纳州的几个州饮用水中 iAs 含量较高的县，严重急性呼吸道综合症的患病率冠状病毒 2 (SARS-CoV-2) 感染率也很高，表明同时暴露于 iAs 和 SARS-CoV-2 发生。这种同时暴露于 iAs 对 SARS-CoV-2 感染易感性和 COVID-19 严重程度的影响从未出现过。被研究过。该提案的目标是描述 iAs 暴露与 SARS-CoV 之间的相互作用 2.使用分化的原代人鼻上皮细胞感染，建立呼吸道体外模型感染，以及一种新型人源化 hAS3MT 小鼠品系，其中 iAs 的代谢及其处置代谢物与人类相似。我们将采用强有力的跨学科方法，采用差异化的方法原代人鼻上皮细胞和人源化 hAS3MT 小鼠，以检验慢性鼻炎的假设接触 iAs 会增加对 SARS-CoV2 感染的易感性和 COVID-19 的严重程度。尽管整合人类和小鼠模型，我们还将研究性别和遗传背景对疾病结果。这两个新的附加目标包括：（目标 1）确定 iAs 及其代谢物对分化的原代人鼻上皮细胞中的 SARS-CoV-2 感染；（目标 2）表征效果 iAs 暴露对 hAS3MT 小鼠 SARS-CoV-2 MA 感染和 COVID-19 结果的影响。在目标 1 中，我们测试假设是接触 iAs 或其代谢物会增强对 SARS-CoV-2 的易感性和严重程度人鼻上皮细胞感染。在目标 2 中，我们将比较免疫反应、病毒滴度、肺暴露于饮用水中的 iAs（0、40 或 400 ppb）并感染了 iAs 的 hAS3MT 小鼠的病理学和死亡率最近在北卡罗来纳大学教堂山分校创建了一种适应小鼠的 SARS-CoV-2。评估性别的作用和遗传学方面，我们将使用具有 C57BL/6NCrl 和 129S6/SvEvTac 背景的雄性和雌性 hAS3MT 小鼠。拟议的研究利用了只有北卡罗来纳大学才有的新颖的实验室模型，并且非常适合用于研究环境 iAs 暴露与 SARS-CoV2 感染之间的相互作用。拟议的研究满足了理解广泛环境之间相互作用的迫切需要暴露和影响全世界数亿人的大流行感染。