The Imprinted Gene Network in the programming of Non-Alcoholic Fatty Liver Disease by early life cadmium exposure

生命早期镉暴露导致非酒精性脂肪肝的印记基因网络

• 批准号: 10166850
• 负责人: Michael Cowley
• 金额: $ 32.2万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-19 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10166850
• 关键词: Adult; Affect; Alleles; Behavior Disorders; Cadmium; Cardiovascular Diseases; Cell Culture Techniques; Cell model; Chemicals; Child; DNA; DNA Methylation; Data; Deposition; Development; Disease; Disease Marker; Disease susceptibility; Dose; Elderly; Environment; Epigenetic Process; Event; Exposure to; Extracellular Matrix; Fatty acid glycerol esters; Functional disorder; Gene Activation; Genes; Genetic; Genetic Transcription; Health; Heavy Metals; Hepatic Stellate Cell; Hepatocyte; Human; Impairment; Inflammation; K-Series Research Career Programs; Kidney; Knowledge; Lead; Life; Link; Lipids; Liver; Longevity; Malignant neoplasm of liver; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; National Institute of Environmental Health Sciences; Nature; Newborn Infant; North Carolina; Onset of illness; Paracrine Communication; Pathway interactions; Patients; Play; Population; Pregnant Women; Production; Program Development; Public Health; Relaxation; Respiratory System; Role; Skeletal system; System; Testing; Therapeutic Intervention; Tissues; Toxic effect; Umbilical Cord Blood; Up-Regulation; Work; World Health Organization; base; developmental disease; disorder prevention; genome-wide; high risk; human data; human model; imprint; improved; in vivo; liver metabolism; mouse model; new therapeutic target; non-alcoholic fatty liver disease; novel; prevent; programs; stressor; toxic metal; toxicant

PROJECT SUMMARY The toxic metal cadmium (Cd) is one of the top ten chemicals of major public health concern identified by the World Health Organization. Cd exerts toxic effects on the kidneys, respiratory and skeletal systems, and long- term exposure is associated with metabolic, cardiovascular and behavioral disorders. We and others have shown that exposure to Cd during early life can lead to disease in adulthood. One of these diseases is non- alcoholic fatty liver disease (NAFLD), characterized by fat accumulation, inflammation and tissue damage in the liver. NAFLD affects 30-40 % of the US adult population, and patients with NAFLD have a higher risk of developing liver cancer. The broad, long-term objectives of this project are to understand the mechanisms that link early life Cd exposure to NAFLD in adulthood, and to use this knowledge to develop strategies that can prevent or reverse this disease. To this end, we have collected data from pregnant women and their children in North Carolina and demonstrated that DNA isolated from newborn cord blood carries molecular `signatures' of Cd exposure. We propose that these signatures play an important role in Cd-induced NAFLD. In the current proposal, we will use mouse and cell culture models to test this hypothesis, and determine how events at the molecular level lead to disease. We propose three specific aims: 1) determine whether the molecular signatures associated with Cd that we observe in humans cause changes to the activity of a set of genes called imprinted genes, which play important roles in liver metabolism; 2) understand how changes to imprinted gene activity lead to NAFLD; and 3) determine whether Cd could cause NAFLD solely through influencing the activity of these genes. We aim to demonstrate that imprinted genes play a central role in linking early life Cd exposure to NAFLD in adulthood, thereby identifying potential markers of disease susceptibility and providing opportunities for treatment prior to disease onset.

项目摘要 有毒金属镉（Cd）是世界卫生组织确定的十大主要公共卫生关注化学品之一。 世界卫生组织。镉对肾脏、呼吸系统和骨骼系统有毒性作用， 长期暴露与代谢、心血管和行为障碍有关。我们和其他人已经 研究表明，在生命早期接触镉会导致成年后的疾病。其中一种疾病是非- 酒精性脂肪肝（NAFLD），其特征是脂肪积聚，炎症和组织损伤， 肝脏NAFLD影响30- 40%的美国成年人群，并且患有NAFLD的患者具有更高的风险， 发展成肝癌本项目的广泛的长期目标是了解 将早期生活中的镉暴露与成年后的NAFLD联系起来，并利用这些知识制定策略， 预防或逆转这种疾病。为此，我们收集了2004年孕妇及其子女的数据， 北卡罗来纳州，并证明从新生儿脐带血中分离的DNA携带的分子“签名”， 镉暴露。我们认为这些信号在镉诱导的NAFLD中起重要作用。在当前 我们将使用小鼠和细胞培养模型来验证这一假设，并确定在实验室中发生的事件是如何发生的。 分子水平导致疾病。我们提出了三个具体目标：1）确定分子是否 我们在人类中观察到的与镉相关的特征会导致一组基因的活性发生变化 称为印迹基因，在肝脏代谢中发挥重要作用; 2）了解印迹基因的变化 基因活性导致NAFLD; 3）确定镉是否可以单独通过影响NAFLD的基因活性而导致NAFLD。 这些基因的活性。我们的目标是证明印记基因在连接早期生命镉中起着核心作用 在成年期暴露于NAFLD，从而确定疾病易感性的潜在标志物， 在疾病发作前获得治疗的机会。