Fetal Adaptation of Chronic Uterine Blood Flow Reduction

描述（由申请人提供）：宫内生长受限（IUGR）是围产期发病和死亡的重要原因。导致子宫胎盘血流量（UtBF）减少的母体条件始终与胎儿生长受限有关。我们研究了由于UtBF减少导致的胎儿持续缺氧对长期插管绵羊胎儿生长的长期影响。通过阻断母端主动脉减少UtBF 7天，导致胎盘质量减少，胎儿供氧减少，胎儿低氧血症，胎儿生长受限，表现为线性生长速率降低-50%。该模型中生长受限的严重程度与胎儿缺氧的程度直接相关。总的假设是，由于慢性UtBF减少导致的胎儿生长限制是对胎儿和胎盘氧气和营养供应不足的生理适应。具体来说，我们假设：1)氨基酸的胎盘运输减少，不仅是因为向胎盘的输送减少，而且也是胎盘运输受损的结果。2)蛋白质合成通过翻译起始受损而受到抑制。结果，胎儿蛋白的增加（因此胎儿生长速度）显著降低。胎儿减少蛋白质合成以应对缺氧的能力是一种生理适应，类似于在“耐缺氧”动物中观察到的。在能量产生减少的情况下，抑制蛋白质合成可减少能量消耗，使胎儿得以存活。我们假设蛋白质合成的适应性下调是翻译起始减少的结果。翻译起始机制受氧、葡萄糖、氨基酸和胰岛素的可用性调节，在骨骼肌中最为明显。我们将通过一系列实验来解决这些假设，在这些实验中，UtBF的减少伴随着主要底物（氧、葡萄糖、氨基酸）和胰岛素的逐步补充。胎盘氨基酸转运，整体胎儿蛋白周转和骨骼肌蛋白动力学，以及蛋白质合成的细胞机制将被测量。这些实验将为子宫血流改变导致胎儿生长受限的机制提供重要而独特的见解。此外，底物替代的逐步制度将阐明在特定底物缺乏的情况下胎儿生长下调的机制。这些数据对于设计人类潜在干预措施以预防和/或减轻胎儿生长受限及其终身后果至关重要。

DESCRIPTION (provided by applicant): Intrauterine growth restriction (IUGR) is a significant cause of perinatal morbidity and mortality. Maternal conditions that result in reduced uteroplacental blood flow (UtBF) are consistently associated with fetal growth restriction. We have examined the long-term effect of sustained fetal hypoxia due to UtBF reduction on fetal growth in the chronically catheterized sheep. Seven days of UtBF reduction through occlusion of the maternal terminal aorta resulted in reduced placental mass, decreased fetal oxygen delivery, fetal hypoxemia, and fetal growth restriction, manifest as a -50% reduction in linear growth rate. The severity of growth restriction in this model is directly related to the degree of fetal hypoxia. The overall hypothesis is that fetal growth restriction due to chronic UtBF reduction is a physiological adaptation to an inadequate supply of oxygen and nutrients to the fetus and placenta. Specifically, we hypothesize that: 1) Placental transport of amino acids is decreased, not only because of diminished delivery to the placenta, but also as a consequence of impaired placental transport. 2) Protein synthesis is inhibited through impaired translation initiation. As a result, fetal protein accretion (and therefore fetal growth rate) markedly decreases. The ability of the fetus to decrease protein synthesis in response to hypoxia is a physiological adaptation similar to that observed in "hypoxia tolerant" animals. Inhibition of protein synthesis reduces energy consumption in the face of diminished energy production, allowing the fetus to survive. We postulate that adaptive down regulation of protein synthesis is a result of decreased translation initiation. The machinery for translation initiation is regulated by the availability of oxygen, glucose, amino acids, and insulin, and will be most apparent in skeletal muscle. We will address these hypotheses by a series of experiments where UtBF reduction is accompanied by a step-wise supplementation of major substrates (oxygen, glucose, amino acids) and insulin. Placental amino acid transport, overall fetal protein turnover and skeletal muscle protein kinetics, as well as the cellular mechanisms of protein synthesis will be measured. These experiments will provide important and unique insight into the mechanisms by which alterations in uterine blood flow lead to fetal growth restriction. Furthermore, the stepwise institution of substrate replacement will elucidate the mechanisms involved in the down regulation of fetal growth in response to specific substrate deficiencies. These data will be crucial in the design of potential interventions in humans to prevent and/or mitigate fetal growth restriction and its lifelong consequences.