Fetal Adaptation of Chronic Uterine Blood Flow Reduction

胎儿对慢性子宫血流量减少的适应

• 批准号: 6640227
• 负责人: DAVID W BOYLE
• 金额: $ 32.17万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640227
• 关键词: adenosine triphosphate; aminoacid transport; blood flow measurement; catheterization; cephalometry; developmental nutrition; embryo /fetus; embryo /fetus protein; genetic translation; glucose transport; immunoprecipitation; insulin; muscle proteins; nutrition related tag; oxygen transport; phosphorylation; placental transfer; pregnancy circulation; pregnancy circulation disorder; prenatal growth disorder; protein biosynthesis; protein metabolism; sheep; striated muscles; translation factor; western blottings

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.

描述(由申请人提供)：宫内生长受限(IUGR)是围产儿发病率和死亡率的重要原因。导致子宫胎盘血流量(UtBF)减少的母体状况一直与胎儿生长受限有关。我们研究了由于UtBF减少而导致的持续性胎儿缺氧对慢性导尿绵羊胎儿生长的长期影响。通过阻断母体末梢主动脉进行UtBF减少7天后，胎盘重量减少，胎儿供氧减少，胎儿低氧血症和胎儿生长受限，表现为线生长速度下降-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减少而导致的胎儿生长受限是对胎儿和胎盘氧气和营养供应不足的生理适应。具体地说，我们假设：1)胎盘对氨基酸的转运减少，不仅是因为对胎盘的输送减少，也是由于胎盘转运受损。2)蛋白质合成因翻译起始功能受损而受到抑制。结果，胎儿蛋白质的增加(因此胎儿生长速度)显著降低。胎儿对低氧的反应减少蛋白质合成的能力是一种生理适应，类似于在“耐低氧”动物中观察到的。在能量生产减少的情况下，抑制蛋白质合成减少了能量消耗，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启动减少的结果。翻译启动的机制受氧气、葡萄糖、氨基酸和胰岛素的可获得性的调节，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(氧气、葡萄糖、氨基酸)和胰岛素的逐步补充。将测量胎盘氨基酸转运、整体胎儿蛋白质周转和骨骼肌蛋白质动力学，以及蛋白质合成的细胞机制。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，循序渐进的底物替代机制将阐明因特定底物缺陷而下调胎儿生长发育的机制。这些数据将对人类预防和/或减轻胎儿生长受限及其终生后果的潜在干预措施的设计至关重要。