Metabolic and Molecular Determinants of Embryo Viability

我们知道，我们成年后的健康受到母亲怀孕期间生活方式的影响。特别是，当出生时瘦小的婴儿在营养摄入不受限制和肥胖的条件下长大时，患糖尿病和心血管疾病等成人发病疾病的风险会增加。这个胎儿计划的概念现在被广泛接受。我们的实验室在一个新概念的研究上处于领先地位，那就是胚胎编程。我们有大量的动物数据表明，胚胎暴露于生理扰动会改变胎儿发育，类似于怀孕期间营养限制所发生的情况。此外，来自体外受精儿童的数据显示，他们的出生体重低于预期，可能是由于实验室受孕的条件所致。卵子和胚胎在受孕时的反应如何影响随后的发育？一些人关注的是与突变无关的DNA变化，而是改变基因表达的DNA结构变化。我们称之为表观遗传学，表观遗传学变化存在于胚胎中，包括体外受精后的人类胚胎。然而，没有人知道这种表观遗传变化是如何由于卵子或胚胎的这种应激反应而发生的。我们的建议是确定表观遗传改变如何在卵子和胚胎中发生的机制。我们的理论是，所有细胞中产生能量的线粒体向胚胎的细胞核发送信号。当卵子或胚胎发现自己处于不利条件时，能量平衡的变化会导致信号的变化。这反过来又改变了细胞核中调节DNA结构的酶的活性。如果我们能证明这种关系的存在，那么我们就能评估人类胚胎中超出患者需求的这些变化，并了解人类胚胎中是否发生了编程。

We know that our health as adults is influenced by the lifestyle of our mothers during pregnancy. In particular, increased risk of adult-onset diseases such as diabetes and cardiovascular disease occurs when small and lean infants at birth are raised in conditions where nutrient intake is not restricted and obesity occurs. This concept of fetal programming is now widely accepted. Our laboratory is leading research in a new concept, that of embryonic programming. We have extensive animal data demonstrating that exposure of embryos to physiological perturbations alters fetal development, similarly to that occurring in nutrient restriction during pregnancy. Furthermore, there is data from IVF-derived children that their birth-weight is lower than expected, possibly due to the conditions used for conception in the laboratory. How does the response by eggs and embryos, at the time of conception, affect subsequent development? There has been some focus on changes to DNA that are not related to mutations, but structural changes in the DNA that alters gene expression. We call this epigenetics and epigenetic changes are found in embryos, including human embryos following IVF. However, no one knows how such epigenetic changes occur as a result of this stress response by the egg or embryo. Our proposal is to determine the mechanism of how epigenetic alterations take place in eggs and embryos. Our theory is that the mitochondria, the energy producing packages within all cells, are sending signals to the embryo's nucleus. When the egg or embryo finds itself in adverse conditions, the signals change as a result of changes in the energy balance. This in turn changes the activity of enzymes in the nucleus that regulates DNA structure. If we can prove that this relationship occurs, then we can assess these changes in human embryos that are excess to a patient's requirements and learn if programming takes place in human embryos.