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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

基本信息

批准号：
10747180
负责人：
Michael Cowley
金额：
$ 8.03万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
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：
2020-05-19 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747180
关键词：
Address Adult Affect Alleles Award Cadmium Cell Line Cell model Cells Chemicals Childhood Data Set Development Disease Elderly Endocrine Disruptors Environment Environmental Exposure Exposure to Fatty acid glycerol esters Functional disorder Genes Genetic Transcription Hepatic Hepatocyte Homeostasis Human Impairment Inflammation K-Series Research Career Programs Knowledge Life Link Lipids Liver Liver diseases Malignant neoplasm of liver Meta-Analysis Metabolic Modeling Molecular Mus National Institute of Environmental Health Sciences Newborn Infant Onset of illness PPAR gamma Parents Pathway interactions Patients Play Population Predisposition Process Procollagen Public Health Risk Role Small Interfering RNA Testing Therapeutic Tissues Toxic Environmental Substances Toxicant exposure Umbilical Cord Blood Work World Health Organization bisphenol A chronic liver disease design druggable target early life exposure environmental stressor gene network high risk imprint in utero in vitro Model in vivo knock-down mouse model non-alcoholic fatty liver disease novel overexpression prevent programs response stressor therapeutic development therapeutic target toxic metal toxicant toxicant screening transcription factor transcriptome

项目摘要

Project summary Non-alcoholic fatty liver disease (NAFLD) is 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. An increasing body of evidence supports a role for the developmental environment in the programming of NAFLD in later life. In support of this, we have demonstrated that exposure to the toxic metal cadmium (Cd) during development causes NAFLD in young mice. Cd is one of the top ten chemicals of major public health concern identified by the World Health Organization, and it has been detected in newborn cord blood, suggesting that Cd exposure in humans can begin during in utero development. In an effort to identify potential therapeutic targets that could prevent the onset of NAFLD in response to developmental Cd exposure, we have studied the underlying molecular mechanisms. We have identified the Imprinted Gene Network (IGN) as a novel player in activating prosteatotic and profibrotic pathways – two of the major pathophysiological processes that underlie NAFLD. However, it is unclear if this mechanism is specific to Cd or if it is relevant to a broader set of toxicants that also program this disease. To address this, we propose three specific aims: 1) perform a meta-analysis of hepatic transcriptome datasets from mouse models of NAFLD programmed by the developmental environment to determine if the IGN is activated in response to a diverse set of stressors; 2) screen toxicants for their ability to activate the IGN in a cell autonomous manner in hepatocytes; 3) use in vitro models of toxicant exposure to test whether prosteatotic and/or profibrotic mechanisms are dependent on the IGN. This work will considerably enhance the impact of the parent award by demonstrating whether this mechanism is specific to Cd or also relevant to a broader set of toxicants. This will be critical knowledge in the drive to identify druggable targets that could be used to prevent the onset of NAFLD after early life exposures.

项目总结