Project 1: Human Fetal Liver and the Metabolic Syndrome

项目1 -人类胎儿肝脏和代谢综合征。本项目的目的是建立和应用一个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方面的作用是公认的。宫内生长迟缓、胎儿代谢规划和后代代谢综合征之间的关联也已建立，近年来已显示涉及表观遗传机制。这个项目的目标是建立一个人类胎儿肝脏异种移植到裸鼠身上的模型。我们将使用该模型来验证一种假设，即与营养环境的改变一样，胎儿砷暴露会诱发胎儿肝脏的表观遗传变化，从而导致成人易患代谢综合征。该建议基于已发表的证据，即胎儿砷暴露会诱发胎儿肝脏的表观遗传变化。该建议还源于我们对胎鼠生长调节信号机制的广泛表征以及我们对胎儿肝细胞表型的新生物标志物的鉴定。我们已经证明，与成年大鼠肝细胞不同，晚期胎儿肝细胞表现出不依赖于有丝分裂原的增殖，并且对雷帕霉素（一种营养感应mTOR通路的抑制剂）的抗增殖作用具有抗性。上述生物标志物包括一些参与生长因子信号传导、细胞周期控制和翻译控制的蛋白质。我们还观察到，雷帕霉素诱导的mTOR抑制以一种与表观遗传机制最一致的方式调节基因表达。我们制定了以下具体目标：具体目标1将建立一个模型，将人胎肝移植到裸鼠体内，并维持胎肝表型（定义如上）。在特异性目标2中，我们将证明对成年大鼠异种移植受体的宿主环境的操纵将诱导胎儿肝脏的变化。我们将研究宿主饮食限制和雷帕霉素给药对胎儿肝脏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与砷暴露影响的表观遗传后果。这个项目的意义在于它有潜力开发一个模型系统来研究人类胎儿肝脏的编程机制，这是现有方法无法做到的。

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 develop 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 fetal 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 rapamycin-induced 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.