Epigenetic mechanisms linking in utero cadmium exposure to hepatic steatosis

项目摘要 此应用程序的目标是促进候选人过渡到一个独立的环境 健康科学（EHS）研究员。他的长期职业目标是应用他在发育生物学方面的技能， 表观遗传学EHS，建立一个研究计划，重点是表观遗传机制，通过 发育期暴露影响终生健康。他的短期目标是训练毒物的机制- 诱导病理学和模拟人类在小鼠中的暴露。他将充分利用EHS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领域的支持， 委员会，具有与提案的各个方面相关的专业知识，涵盖毒理学，基因组学，环境 表观遗传学和人口健康科学。候选人将参加课程“分子与 生物化学毒理学“，出席会议，并组织一个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。他会用表观遗传学 尚未被EHS社区广泛采用的工具，以证明其对该领域的价值。的 该项目将确定子宫内暴露于环境相关剂量的镉（Cd）是否可以编程 肝脂肪变性，并将确定表观遗传变化如何影响基因的转录调节 肝脏脂质代谢该项目将集中在印记基因，表达从只有一个等位基因，这是 表观遗传修饰的镉和肝脏脂质储存的关键调节剂。假设在子宫内 小鼠镉暴露破坏了印记控制区的DNA甲基化，引起了一种新的免疫调节机制的失调。 印迹基因的网络，这有助于在成年期肝脂肪变性的编程。 为了解决这个问题，将使用一个遗传模型，使研究印迹基因不可能与 标准小鼠模型。具体目标是：目标1：确定子宫内镉暴露是否足以 胎儿和成年期的程序性肝脂肪变性。目的2：确定镉诱导的DNA 印迹控制区的甲基化改变破坏了印迹基因的等位基因特异性转录 网络在子宫内的发展，有助于镉暴露的病理生理效应。 长期目标是建立人类子宫内暴露的小鼠模型，以了解 成人疾病的镉方案剂量。镉的作用机制尚不明确，研究 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成肝细胞和肝细胞中，我们将确定是否 这些变化反映在外周血中，这对于鉴定 可获取的组织。该应用程序包括一个综合的职业发展和研究计划，使 候选人将其现有的技能应用于EHS，以发展一个对NIEHS R 01资金有竞争力的利基市场。

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.