Project 1: Human Fetal Liver and the Metabolic Syndrome

项目1 -人类胎儿肝脏和代谢综合征。本项目的目的是开发和使用一种模型来研究砷对胎儿肝脏发育的影响。该项目是基于胎儿肝脏发育改变与后代代谢综合征风险之间的关系。肝脏在代谢调节和胰岛素敏感性中的作用已得到充分证实。胎儿宫内发育迟缓，胎儿代谢编程和代谢综合征的后代之间的关联也被建立，近年来已被证明涉及表观遗传机制。本课题的目的是建立人胎肝移植到裸鼠体内的模型。我们将使用这个模型来检验这一假设，如在营养环境的改变，胎儿砷暴露诱导胎儿肝脏的表观遗传变化，易患代谢综合征在成人的建议是基于已发表的证据表明，胎儿砷暴露诱导胎儿肝脏的表观遗传变化。该建议还来自我们对胎鼠生长调节信号机制的广泛表征以及我们对胎肝细胞表型的新生物标志物的鉴定。我们已经表明，晚期胎肝细胞，不像成年大鼠肝细胞，显示分裂原非依赖性增殖和耐雷帕霉素的抗增殖作用，营养敏感的mTOR通路的抑制剂。上述生物标志物包括参与生长因子信号传导、细胞周期控制和翻译控制的许多蛋白质。我们还观察到雷帕霉素诱导的mTOR抑制以与表观遗传机制最一致的方式调节基因表达。我们已经开发了以下具体目标：具体目标1是开发一种模型，其中将人胎肝移植到裸大鼠中，并保持胎肝表型（如上定义）。在特定目标2中，我们将证明在成年大鼠异种移植受体中操纵宿主环境将诱导胎肝的变化。我们将检查宿主饮食限制和雷帕霉素给药的影响，以检查对胎肝生长和基因表达的影响 具体目标3将是表征和对比宿主饮食限制和雷帕霉素的表观遗传后果与砷暴露的影响。这个项目的意义在于它有可能开发一个模型系统来研究人类胎肝编程的机制，这是现有方法学所无法实现的。

PROJECT 1 - Human Fetal Liver and the Metabolic Syndrome. The purpose of this project is to develop and employ a model for studying the effects of arsenic on fetal liver development. The project is predicated on the relationship between altered fetal liver development and risk for metabolic syndrome in the offspring. The role of the liver In metabolic regulation and insulin sensitivity is well established. The association between intrauterine growth retardation, fetal metabolic programming and metabolic syndrome in the offspring is also established, having been shown in recent years to involve epigenetic mechanisms. The goal of this project is to deveiop a model in which human fetal liver is xenografted to nude rats. We will use this model to test the hypothesis that, like alterations in the nutrient environment, fetal arsenic exposure induces epigenetic changes in fetai liver that predispose to metabolic syndrome in the adult The proposal is based on published evidence that fetal arsenic exposure induces epigenetic changes in fetal liver. The proposal also derives from our extensive characterization of growth-regulating signaling mechanisms in the fetal rat and our identification of novel biomarkers for the fetal hepatocyte phenotype. We have shown that late term fetal hepatocytes, unlike adult rat hepatocytes, show mitogenindependent proliferation and are resistance to the anti-proliferative effects of rapamycin, an inhibitor of the nutrient-sensing mTOR pathway. The aforementioned biomarkers include a number of proteins involved in growth factor signaling, cell cycle control and translation control. We have also observed that rapamycininduced inhibition of mTOR modulates gene expression in a manner most consistent with epigenetic mechanisms. We have developed the following specific aims: Specific Aim 1 will be to develop a model in which human fetal liver is transplanted into nude rats and the fetal liver phenotype (defined as above) is maintained. In Specific Aim 2, we will demonstrate that manipulation of the host environment in the adult rat xenograft recipients will induce changes in fetal liver. We will examine the effects of host dietary restriction and rapamycin administration to examine the effect on fetal liver growth and gene expression Specific Aim 3 will be to characterize and contrast the epigenetic consequences of host dietary restriction and rapamycin with the effects of arsenic exposure. The significance of this project lies in its potential to develop a model system to study mechanisms for programming of human fetal liver, something that is not possible with available methodologies.