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

项目总结 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，而且长期- 长期暴露与代谢、心血管和行为障碍有关。我们和其他人有 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 酒精性脂肪性肝病(NAFLD)，以脂肪堆积、炎症和组织损伤为特征 肝脏。NAFLD影响美国30%-40%的成年人口，NAFLD患者患上NAFLD的风险更高 患上了肝癌。该项目的广泛、长期目标是了解 将成年早期接触CD与非酒精性脂肪肝联系起来，并利用这一知识制定策略，以 预防或逆转这种疾病。为此，我们收集了#年孕妇及其子女的数据。 并证明了从新生儿脐带血中分离出的DNA携带着 CD曝光。我们认为这些信号在Cd诱导的NAFLD中起着重要作用。在当前 提案中，我们将使用小鼠和细胞培养模型来验证这一假设，并确定 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 我们在人类身上观察到的与CD相关的信号会导致一组基因活性的变化 称为印迹基因，它在肝脏新陈代谢中发挥重要作用；2)了解印迹基因如何改变 基因活性导致NAFLD；3)仅通过影响Cd对NAFLD的影响来确定Cd是否可导致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CD中起核心作用。 成年期接触非酒精性脂肪肝，从而确定疾病易感性的潜在标志，并提供 在疾病发作前获得治疗的机会。

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.