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REGULATION OF ERYTHROPOIETIN GENE EXPRESSION IN FETUS

胎儿促红细胞生成素基因表达的调控

基本信息

批准号：
2889212
负责人：
ROBERT A BRACE
金额：
$ 24.98万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2001-03-31
项目状态：
已结题

项目摘要

Erythropoiesis in the fetus and adult is regulated by the hormone erythropoietin (Epo). In the adult, Epo is produced in the kidney. Epo in the fetus is believed to be produced mainly by the liver, with the kidneys becoming an important source only late is gestation. However, with molecular techniques, high levels of Epo gene expression are found in the fetal kidney throughout gestation whereas Epo gene expression in the fetal liver is low. Further, new studies suggest that the placenta, which is fetal tissue, produces Epo. The factors which stimulate Epo production are hypoxia and anemia. However, the characteristics of the hypoxic and anemic effects on Epo gene expression have not been examined in the fetus. The proposed studies are designed to explore the regulation of Epo gene expression and plasma Epo concentration in the ovine fetus by combining physiological and molecular approaches. Specific Aim 1 will establish the normal patterns of Epo gene expression in placenta, fetal liver and kidneys from 50 days gestation to term (150 days). The techniques of Northern analysis and competitive reverse transcription-polymerase chain reaction will be used for the quantification of Epo messenger RNA (mRNA). The localization of the cell types which express Epo mRNA and protein will be accomplished by the methods of in situ hybridization and immunohistochemistry. The hypothesis is that each tissue displays different patterns across gestation. Specific Aim 2 will explore the effects of fetal hypoxia induced by maternal hypoxemia on Epo mRNA abundance in kidney, liver and placenta of fetuses from 100 to 150 days gestation. The hypothesis is that Epo gene expression will be enhanced more in the placenta and fetal kidney than in the liver. Specific Aim 3 will explore Epo gene expression responses to hypoxia induced by fetal anemia in fetuses from 100-150 days gestation. The hypothesis is that fetal anemia induces Epo mRNA in the kidney and liver but not the placenta. Our overall hypothesis is that the placenta, fetal liver and kidney differentially express Epo across gestation and that the hypoxic induction of Epo gene expression in each tissue depends on the type of hypoxia. These studies are significant because they could significantly improve our understanding of the regulation of Epo and red cell production in the fetus and are important because they could help improve the diagnosis and treatment of human fetuses and neonates with anemia and/or hemolytic disease, thereby improving perinatal outcome.

胎儿和成人的红细胞生成受激素调节促红细胞生成素（Epo）。在成年人中，Epo在肾脏中产生。 EPO 据信，胎儿体内的胰岛素主要由肝脏产生，肾脏在妊娠后期才成为重要的来源。然而，在这方面，通过分子生物学技术，在整个妊娠期胎儿肾脏中发现，而Epo基因在胎儿肝脏中的表达是低的。此外，新的研究表明，胎盘，也就是胎儿组织，产生促红细胞生成素的因素刺激Epo产生是缺氧和贫血。但缺氧和贫血对Epo基因影响的特点尚未在胎儿中检测到表达。拟议的研究旨在探索Epo基因表达的调控，通过结合生理学方法测定绵羊胎儿血浆Epo浓度和分子方法。具体目标1将建立正常的 Epo基因在胎盘、胎儿肝脏和肾脏中的表达模式从妊娠50天到足月（150天）。北方的技术分析和竞争性逆转录聚合酶链反应将用于定量Epo信使RNA （mRNA）。表达Epo mRNA的细胞类型的定位和蛋白质将通过原位方法完成杂交和免疫组织化学。假设是，组织在整个妊娠期表现出不同的模式。具体目标2将探讨母体低氧血症致胎儿缺氧对胎儿生长发育的影响不同胎龄胎儿肾脏、肝脏和胎盘中Epo mRNA丰度的差异妊娠100至150天。假设Epo基因表达在胎盘和胎儿肾脏中比在肝脏具体目标3将探索Epo基因表达反应， 100-150天胎儿贫血引起缺氧怀孕假设胎儿贫血诱导Epo mRNA表达，肾脏和肝脏但胎盘不行我们的总体假设是胎盘、胎儿肝脏和肾脏表达Epo的差异缺氧诱导Epo基因表达取决于缺氧的类型这些研究因为它们可以大大提高我们对的调节Epo和红细胞的生产在胎儿和因为它们可以帮助改善诊断和治疗患有贫血和/或溶血性疾病的人类胎儿和新生儿，从而改善围产期结果。