Heavy metals exposure regulates secretory lineage in intestinal injury

重金属暴露调节肠道损伤的分泌谱系

• 批准号: 10662074
• 负责人: Julie Goeun In
• 金额: $ 15.25万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662074
• 关键词: 3-Dimensional; Address; Affect; Apical; Bacterial Adhesion; Biodiversity; Biological; Cell Differentiation process; Cell Line; Cells; Chemical Exposure; Chemical Injury; Chronic; Coculture Techniques; Colitis; Colon; Colorectal Cancer; Communities; Disease; Dust; Endocrine; Enterochromaffin Cells; Enteroendocrine Cell; Environment; Epithelial; Epithelial Cells; Exposure to; Functional disorder; Genetic; Genetic Variation; Goals; Goblet Cells; Heavy Metals; Homeostasis; Hormone secretion; Hormones; Human; Immune; In Vitro; Incidence; Individual; Inflammatory; Inflammatory Response; Ingestion; Inhalation; Injury; Intestinal Diseases; Intestinal Secretions; Intestines; Ligands; Link; Metal exposure; Metals; Minerals; Modeling; Molecular; Mucous Membrane; Mucous body substance; Organoids; Particulate; Pathology; Pathway interactions; Permeability; Population; Predisposition; Prevalence; Prevention; Role; Serotonin; Site; Surface; Testing; Thinness; Toxic Environmental Substances; United States; Uranium; Water; cytokine; epidemiologic data; ground water; gut inflammation; gut microbiota; healing; human data; immunological status; intestinal barrier; intestinal epithelium; intestinal injury; macrophage; microbial; microbiota; monolayer; novel strategies; pathogen; response; response to injury; therapeutic target; tool; transcriptomics; tribal lands; two-dimensional; underserved community; wasting

PROJECT SUMMARY Over 160,000 abandoned mine waste sites are concentrated in the western United States and continue to degrade the environment with elevated heavy metals penetrating the surrounding sediment and groundwater. The sedimentary dust and water used by communities located near abandoned uranium mine (AUM) sites often exceeds the maximum contamination level for uranium (U, EPA max level 30 μg/L). Chronic exposure to environmental toxins and heavy metals has been linked to intestinal inflammation, increased susceptibility to pathogen-induced diseases, and higher incidences of colorectal cancer; all of which have been steadily increasing in prevalence for the past 40 years. The negative effects of heavy metals on the intestinal microbiota, barrier permeability, and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells are largely unknown. Upon ingestion, uranium is poorly absorbed systemically (~1.5%) and thus distributed through the entire intestine, suggesting even low U levels are sufficient to cause intestinal damage. Thus, our goals are to characterize particulate dust (referred to as U-bearing dust, UBD) as an environmental toxicant that damages the intestinal epithelia and determine the molecular changes that develop as a response to this injury. We have previously characterized the intestinal mucus layer in human intestinal organoids (HIOs) under homeostasis and pathogen infected conditions, to characterize HIOs as an intestinal pathophysiological model. Our preliminary data of HIOs exposed to UBD found that chemical exposure negatively impacts the secretory lineage in the colon, specifically the mucus- producing goblet cells and hormone-producing enteroendocrine cells. Thus, we hypothesize that UBD has a direct effect on: 1) the mucosal surface, represented by a thinning mucus layer and goblet cell dysfunction and 2) the intestinal enteroendocrine cells in the crypt. This leads to increased susceptibility to intestinal disorders. The following Aims will address these questions in a mechanistic manner. The first aim will determine the impact of UBD on mucus layer thinning, resulting pro-inflammatory response, and subsequent goblet cell expansion. The second aim will examine the roles of increased endocrine hormone secretion for intestinal healing and the specific pathway that direct enteroendocrine cell expansion following UBD chemical injury. There is a need to understand how heavy metals, especially those naturally occurring as particulates, drive changes in exposed individuals to predispose them to intestinal disorders and to develop novel strategies that will aid in prevention. Successful completion of this proposal will help us understand the mechanistic underpinnings of environmental-induced injury that may promote colitis or related diseases, identify potential therapeutic targets, and identify genetic variations that may contribute to susceptibility.

项目摘要 超过160,000个废弃的矿石废物集中在美国西部，并继续 用升高的重金属穿透周围沉积物和地下水，使环境降低。 位于废弃铀矿（AUM）地点附近的社区使用的沉积灰尘和水 慢性暴露通常超过铀的最大污染水平（U，EPA最大水平30μg/L）。 环境毒素和重金属与肠道注射有关，对 病原体诱发的疾病和大肠癌的发动机较高；所有这些都是稳定的 过去40年的患病率增加。重金属对肠道的负面影响 已经描述了微生物群，屏障渗透性和抑制肠上皮愈合。然而， 肠上皮细胞内的转录组变化在很大程度上未知。摄入后，铀是 系统地吸收不良（约1.5％），因此通过整个肠道分布，表明u 水平足以造成肠道损伤。那就是我们的目标是表征特定的灰尘（称为 作为含有U的灰尘，UBD）是一种损害肠上皮并确定的环境有毒物 作为对这种损伤的反应而发展的分子变化。我们以前已经表征了肠道 在体内稳态和病原体感染条件下人类肠癌（HIO）中的粘液层 将HIO视为肠道病理生理模型。我们暴露于UBD的HIO的初步数据 发现化学暴露对结肠的秘密谱系产生负面影响，特别是粘液 - 产生杯状细胞和产生马内分泌细胞。那，我们假设UBD有一个 直接影响：1）粘膜表面，由粘液层变薄和杯状细胞功能障碍表示 2）地下室中的肠肠内分泌细胞。这导致对肠道的敏感性增加 疾病。以下目标将以机械方式解决这些问题。第一个目标 确定UBD对粘液层变薄的影响，导致促炎反应，然后 杯状细胞扩展。第二个目标将研究内分泌激素分泌增加的作用 肠道愈合和UBD化学后直接肠内分泌细胞扩展的特定途径 受伤。有必要了解重金属，尤其是那些自然出现的细节的金属， 推动暴露个人的变化，使他们偏爱肠道疾病并制定新型策略 这将有助于预防。成功完成此建议将有助于我们了解机械 环境诱发的损伤的基础，可能促进结肠炎或相关疾病，确定潜力 治疗靶标，并确定可能导致易感性的遗传变异。