Epigenetic mechanisms linking in utero cadmium exposure to hepatic steatosis

子宫内镉暴露与肝脂肪变性相关的表观遗传机制

• 批准号: 9754836
• 负责人: Michael Cowley
• 金额: $ 16.17万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754836
• 关键词: Address; Adopted; Adult; Affect; Alleles; Biochemical; Biological Process; Blood; Cadmium; Cells; Cirrhosis; Communities; DNA; DNA Methylation; Data; Development; Development Plans; Developmental Biology; Disease; Dose; Educational workshop; Elderly; Elements; Environment; Environmental Health; Epigenetic Process; Exposure to; Fatty Liver; Fetus; Funding; GRB10 gene; Gene Expression Regulation; Genes; Genetic Models; Genetic Transcription; Genomics; Goals; Grant; Health; Health Sciences; Hepatic; Hepatocyte; Human; Knowledge; Life; Link; Lipids; Liver; Liver diseases; Maps; Mediating; Methylation; Mission; Molecular; Mus; National Institute of Environmental Health Sciences; Newborn Infant; Outcome; Outcome Study; Pathology; Physiological; Problem Solving; Research; Research Personnel; Research Project Grants; Risk; Risk Assessment; Risk Factors; Role; Sampling; Tissues; Toxicology; Training; Training Programs; Umbilical Cord Blood; Work; base; biomarker identification; career; career development; cohort; epigenome; exposed human population; fetal; genome-wide; human model; imprint; in utero; insight; lipid metabolism; meetings; mouse model; non-alcoholic fatty liver disease; novel; novel therapeutics; peripheral blood; population health; prenatal; prenatal exposure; prevent; programs; ranpirnase; research and development; response; skills; tool; toxic metal; toxicant; whole genome

PROJECT SUMMARY The goal of this application is to facilitate the transition of the candidate to an independent environmental health science (EHS) researcher. His long-term career goal is to apply his skills in developmental biology and epigenetics to EHS, building a research program focused on the epigenetic mechanisms through which developmental exposures affect life-long health. His short-term goal is to train in mechanisms of toxicant- induced pathology and modeling human exposures in the mouse. He will capitalize on the EHS environment at NCSU, including the Center for Human Health and the Environment (CHHE; funded by an NIEHS P30) and the NIEHS T32 Training Grant. Key elements of the career development plan include support from a diverse committee, with expertise relating to all aspects of the proposal, spanning toxicology, genomics, environmental epigenetics and population health science. The candidate will participate in the course `Molecular & Biochemical Toxicology', present at meetings, and organize an environmental epigenetics workshop. The candidate's research project integrates with his career goals and training program. He will use epigenetics tools that have not been widely adopted by the EHS community, to demonstrate their value to the field. The project will determine if in utero exposure to environmentally-relevant doses of cadmium (Cd) can program hepatic steatosis, and will determine how epigenetic changes affect the transcription of genes regulating hepatic lipid metabolism. The project will focus on imprinted genes, expressed from only one allele, which are epigenetically modified by Cd and are critical regulators of liver lipid storage. The hypothesis is that in utero Cd exposure in mice disrupts DNA methylation at imprinting control regions, causing dysregulation of a network of imprinted genes, which contributes to the programming of hepatic steatosis in adulthood. To address this, a genetic model will be used that enables studies of imprinted genes not possible with standard mouse models. The specific aims are: Aim 1: Determine if in utero Cd exposure is sufficient to program hepatic steatosis in the fetus and in adulthood. Aim 2: Determine whether Cd-induced DNA methylation changes at imprinting control regions disrupt allele-specific transcription of the imprinted gene network during in utero development, contributing to the pathophysiological effects of Cd exposure. The long-term objective is to establish a mouse model of human in utero exposure to understand how low doses of Cd program adult disease. The mechanisms of action of Cd are poorly defined, and the study is therefore relevant to the mission of the NIEHS. While the focus of this proposal will be on epigenetic changes in hepatoblasts and hepatocytes, which are most relevant to the study of steatosis, we will determine whether these changes are reflected in peripheral blood, which will be important for the identification of biomarkers in accessible tissues. The application includes an integrated career development and research plan, enabling the candidate to apply his existing skills to EHS to develop a niche that is competitive for NIEHS R01 funding.

项目总结 此应用程序的目标是促进候选人向独立环境的过渡 健康科学(EHS)研究员。他的长期职业目标是将他的技能应用于发育生物学和 表观遗传学到EHS，建立一个专注于表观遗传学机制的研究计划，通过 发育阶段的暴露会影响终生健康。他的短期目标是训练毒物的机制- 在小鼠中诱导病理和模拟人类暴露。他将利用EHS的环境， NCSU，包括人类健康和环境中心(CHHE；由NIEHS P30资助)和 NIEHS T32培训补助金。职业发展计划的关键要素包括来自不同方面的支持 委员会，与提案的所有方面有关的专业知识，横跨毒理学、基因组学、环境 表观遗传学和人口健康科学。候选人将参加`分子与分子‘课程。 生物化学毒理学，出席会议，并组织环境表观遗传学研讨会。 候选人的研究项目与他的职业目标和培训计划相结合。他将使用表观遗传学 EHS社区尚未广泛采用的工具，以证明其在现场的价值。这个 该项目将确定在子宫内暴露于与环境相关的剂量的镉(Cd)是否可以规划 肝脏脂肪变性，并将决定表观遗传变化如何影响调控基因的转录 肝脂代谢。该项目将专注于印记基因，只表达一个等位基因，这是 由CD表观遗传修饰，是肝脏脂肪储存的关键调节因子。假设是在子宫内 小鼠接触Cd会破坏印迹控制区的DNA甲基化，导致A 印记基因网络，这有助于成年后肝脏脂肪变性的编程。 为了解决这一问题，将使用一种遗传模型，使研究印记基因成为可能，而 标准鼠标模型。具体目标是：目标1：确定宫内镉暴露是否足以 在胎儿和成年期规划肝脏脂肪变性。目的2：确定镉诱导的DNA 印迹控制区的甲基化改变打乱了印迹基因的等位基因特异性转录 在子宫内发育过程中，Cd对Cd暴露的病理生理效应起到了促进作用。 长期目标是建立一个人类子宫内暴露的小鼠模型，以了解多低的 剂量的CD程序成人疾病。镉的作用机制还不清楚，这项研究是 因此与NIEHS的使命相关。虽然这项提案的重点将是表观遗传变化 在与脂肪变性研究最相关的肝母细胞和肝细胞中，我们将确定 这些变化反映在外周血中，这将是重要的生物标记物的识别。 无障碍纸巾。该应用程序包括一个综合的职业发展和研究计划，使 候选人将他现有的技能应用于EHS，以开发对NIEHS R01资金具有竞争力的利基市场。