Molecular mechanisms of adaptation to intrauterine and perinatal changes of oxygen partial pressure: The liver-to-kidney switch of Erythropoietin production as model system

点击翻译按钮获取中文摘要

INTRODUCTION: The adequate oxygen homeostasis is essential for proper intrauterine development. The adaptation to placental oxygenation is precisely regulated by complex molecular mechanisms that control oxygen sensing and expression of oxygen-dependent genes. The response to intrauterine hypoxia modifies a developmental program that should, ontogenetically, only dramatically change at term when the body is prepared to switch to high oxygen partial pressure (pO2) of air-breathing life. In very preterm infants, the immediate stop of proper expression of oxygen-dependent genes such as Vascular Endothelial Growth Factor (VEGF) or Erythropoietin (EPO) causes characteristic diseases that may have life-long consequences for neurodevelopmental outcome and significant morbidities. To study the pathophysiology of disorders of oxygen homeostasis, regulation of EPO is an intriguing model system. EPO gene transcription is modulated by the oxygen sensing system which includes the Prolyl Hydroxylases (PHDs) and Hypoxia Inducible Factor (HIF). The HIF-dependent EPO expression is subject to significant changes in the response to oxygen availability (higher production capacity in kidneys), but also to blood perfusion (liver-to-kidney switch). Thus, the EPO model will be utilized to elucidate the adaptation of the oxygen sensing system of the fetus and neonate under hypoxia and hyperoxia that are highly relevant for diseases of very preterm infants. METHODS and WORK PROGRAMME: Embryos/fetuses from timed-pregnant mice will be studied under conditions of modulated oxygen sensing during development by using a PHD inhibitor to stabilize HIF (and thereby mimic hypoxia) or hyperoxia to destabilize HIF. HIF stabilization and hyperoxia both imitate disturbed fetal or early neonatal oxygen homeostasis. The effects of such treatments have not been studied before. In detail, we will examine the impact of intrauterine and perinatal changes of the pO2 on the adaptive response of the HIF-PHD oxygen sensing system. We will contrast the influence of acute and chronic pO2 changes during development by short- or long-term exposure of pregnant mice to HIF stabilization or degradation vs. normal conditions. It will also be of interest to combine disturbed fetal oxygenation with acute perinatal hypoxia or hyperoxia. Downstream of the HIF-PHD system, we will dissect the Epo production and the molecular mechanisms of the two developmental switches of Epo expression: 1) from high, mostly hypoxia-independent to lower, but hypoxia-dependent expression during liver development, and 2) from the liver to the kidney. OBJECTIVES: With this research project, we will gain knowledge on the complex regulation of oxygen sensing and Epo production during development. The results will be highly relevant for the understanding of the general pathophysiology of characteristic diseases of very premature infants. This will ultimately inspirit novel treatment concepts for improved long-term outcomes.