The Epitranscriptome as a Novel Mechanism of Arsenic-Induced Diabetes.

表观转录组作为砷诱发糖尿病的新机制。

• 批准号: 10322037
• 负责人: Andrea Baccarelli
• 金额: $ 64.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322037
• 关键词: Adult; Affect; Albuminuria; American Indians; Arizona; Arsenic; Beta Cell; Biological; Blood; Blood Cells; Cause of Death; Cellular Stress Response; Childhood; Clinical; Clinical Data; Clinical Markers; Communities; DNA Methylation; Data; Development; Diabetes Mellitus; Disputes; Elderly man; Environmental Pollution; Exposure to; Fatty acid glycerol esters; Fingerprint; Follow-Up Studies; Food; Functional disorder; Funding; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glucose; Glycosylated Hemoglobin; Heart; Hepatic; Human; Immune response; Individual; Inflammation; Insulin; Insulin Resistance; Intervention; Joints; Life; Link; Lipids; Liver; Longitudinal Studies; Machine Learning; Measures; Mendelian randomization; Messenger RNA; Metabolic Marker; Metabolic dysfunction; Metabolic syndrome; Modification; Names; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oklahoma; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Phenotype; Pilot Projects; Plasma; Play; Population; Prevalence; Preventive; Process; Proteins; RNA; RNA Stability; Reader; Recommendation; Research; Resources; Risk; Role; Savings; Schedule; Serum; Severities; Shapes; South Dakota; System; Testing; Tissues; Transcript; Translations; United States; Visit; Water; Whole Blood; blood glucose regulation; cohort; data infrastructure; design; diabetes mellitus therapy; epigenomics; epitranscriptome; epitranscriptomics; histone modification; insight; multidimensional data; novel; phenotypic data; preventive intervention; response; statistical and machine learning; systemic inflammatory response; toxicant

SUMMARY In the United States, the prevalence of type 2 diabetes mellitus (T2DM) is particularly high among American Indian (AI) communities. Arsenic (As), a pervasive environmental contaminant disproportionately affecting AI communities, may explain this increased risk. Arsenic induces oxidative stress and systemic low-grade inflammation leading to β-cell dysfunction and insulin resistance in target tissues. However, the impact of As on T2DM has been disputed due to a lack of coherent mechanism for these findings. Previous studies have focused on epigenomic mechanisms (e.g., DNA methylation, histone modifications), overlooking downstream regulatory mechanisms that can more directly shape phenotypes. We propose to investigate the RNA modification N6- methyladenosine (m6A), the most prevalent epitranscriptomic modification on messenger RNA, which is directly involved in the cellular stress response. In experimental systems, arsenic induces a m6A response. m6A also modulates key processes underlying T2DM pathogenesis, including immune response and systemic inflammation. m6A is controlled by a group of proteins called reader, writer, and erasers (RWEs), responsible for adding, interpreting, and removing m6A marks. Fat mass and obesity-associated protein (FTO) is one example of an arsenic-sensitive m6A eraser with strong ties to T2DM and glucose homeostasis. Our pilot study in elderly men exposed to low-level arsenic supported these findings. We propose to test the hypothesis that altered m6A and RWEs are plausible mechanisms for As-related T2DM in the Strong Heart Study (SHS). The SHS is an ongoing longitudinal study in AI communities in Arizona, Oklahoma, and North/South Dakota with detailed clinical data for T2DM and metabolic syndrome (MetS). The SHS has measured speciated As exposure data covering childhood and adult exposure windows, both independently associated with T2DM in previous research. Leveraging the cohort design, exposure and phenotypic data, infrastructure, and study team, we propose to conduct epitranscriptomic analysis of mRNA m6A profiles via m6A sequencing and measure mRNA expression of 20 RWEs using whole blood from 1100 participants at the upcoming SHS follow up visit (scheduled for 2022- 23). Our specific aims are to: 1) determine the association of past and current As exposure with epitranscriptomic profiles of m6A and RWEs mRNA expression levels in blood; 2) determine the association of blood m6A epitranscriptomic profiles with metabolic markers and MetS, clinical T2DM prevalence, and T2DM control (glycated hemoglobin, albuminuria); 3) develop a predictive m6A fingerprint that quantifies the risk of T2DM due to As exposure using machine learning approaches. For aims 1 and 2 we will further use Mendelian randomization to assess causal relationships. Characterization of m6A profiles in a population of AI adults highly impacted by T2DM will reveal biological features linking a pervasive toxicant such as As to diabetes. In addition to leading to interventions to reduce As exposure in the US and globally, defining the roles of m6A and RWEs in T2DM may contribute to new targets for future diabetes therapies.

概括 在美国，美国2型糖尿病（T2DM）的患病率在美国的患病率特别高 印度（AI）社区。砷（AS），一种普遍的环境污染物不成比例地影响AI 社区可以解释这种增加的风险。砷诱导氧化应激和全身低级 炎症导致目标时机中β细胞功能障碍和胰岛素抵抗。但是，AS的影响 由于缺乏这些发现的相干机制，T2DM引起了争议。以前的研究集中 关于表观基因组机制（例如DNA甲基化，组蛋白修饰），俯瞰下游调节 可以更直接塑造表型的机制。我们建议研究RNA修饰N6- 甲基腺苷（M6A），这是信使RNA上最普遍的表面转录体修饰，直接是直接的 参与细胞应激反应。在实验系统中，砷诱导M6A反应。也是M6A 调节T2DM发病机理的基础关键过程，包括免疫反应和全身性 炎。 M6A由一组名为读者，作家和橡皮擦（RWES）的蛋白质控制，负责 添加，解释和删除M6A标记。脂肪质量和肥胖相关蛋白（FTO）是一个例子 与T2DM和葡萄糖稳态有牢固联系的砷敏感的M6A橡皮擦。我们的试点研究 暴露于低级砷的男性支持了这些发现。我们建议检验改变M6A的假设 RWES是强大心脏研究（SHS）中与AS相关T2DM的合理机制。 SHS是 在亚利桑那州，俄克拉荷马州和南达科他州的AI社区正在进行的纵向研究，并具有详细的临床 T2DM和代谢综合征（METS）的数据。 SHS测量了指定的曝光数据覆盖 在先前的研究中，童年和成人曝光窗口都与T2DM独立相关。 利用队列设计，曝光和表型数据，基础设施和研究团队，我们建议 通过M6A测序和测量mRNA表达进行mRNA M6A谱的表面参考分析 在即将到来的SHS后续访问中使用来自1100名参与者的全血的20个RWE（预定于2022- 23）。我们的具体目的是：1）确定过去和电流作为暴露与表面参考的关联 血液中M6A和RWES mRNA表达水平的特征； 2）确定血液M6A的关联 具有代谢标记物和MetS，临床T2DM患病率和T2DM控制 （糖化血红蛋白，蛋白尿）； 3）开发一种预测性M6A指纹，该指纹量化T2DM的风险 使用机器学习方法作为接触。对于目标1和2，我们将进一步使用Mendelian 随机分组以评估因果关系。 AI成人人群中M6A剖面的表征很高 受T2DM的影响将揭示与糖尿病等普遍有毒物质相关的生物学特征。此外 导致干预措施减少美国和全球的暴露，定义M6A和RWES的作用 T2DM可能为未来糖尿病疗法的新靶标做出贡献。