Inositol-preventable neural tube defects: understanding the molecular causes and mechanisms of prevention

在怀孕早期，胚胎发育中的一个关键事件是神经管的形成，神经管随后将发育成大脑和脊髓。神经管未能正确形成导致一组称为神经管缺陷（NTD）的出生缺陷，其中胎儿的大脑和/或脊髓受到不可逆的损伤，导致出生前或出生后不久死亡，或存活婴儿的残疾。总体而言，NTD发生率约为1/1，000，尽管发生率各不相同，并且在某些地区（例如北方爱尔兰和苏格兰）明显更高。在全球范围内，每年约有13万例病例发生。NTD的风险取决于遗传遗传因素和非遗传因素，如饮食，但确切的原因还不清楚。然而，如果母亲在怀孕前和怀孕早期服用叶酸补充剂，受影响怀孕的风险可以大大降低。不幸的是，并非所有NTD病例都可以通过叶酸预防，因此，我们正在寻求其他保护方法。使用自然产生叶酸抗性NTDs的小鼠模型，我们发现另一种维生素肌醇可以预防NTDs，我们现在正在进行临床试验，以测试肌醇是否可以预防人类NTDs。本研究建议有两个主要目的。首先，我们将调查小鼠中肌醇可预防NTD的原因。我们使用了一种技术，可以让我们分离许多蛋白质，并比较哪些蛋白质存在于正常胚胎和发育NTD的胚胎中。我们已经检测到几种蛋白质，似乎是目前在较低的丰度或异常修饰的形式在胚胎发育NTD。我们将在这些研究的基础上，通过分析在发生脊柱裂的胚胎中似乎异常的蛋白质。了解特定蛋白质在小鼠中的作用可能表明人类中的风险因子基因。这项研究的第二个目的是准确地找出肌醇是如何预防NTD的，因为这可能会使治疗方法得到改进。了解人类NTD的原因，可以为考虑再次怀孕的受影响家庭提供更准确的咨询，并可以确定哪些妇女将受益于肌醇补充剂。

During early pregnancy, a crucial event in the developing embryo is the formation of the neural tube , which will later develop into the brain and spinal cord. Failure of the neural tube to form correctly leads to a group of birth defects called neural tube defects (NTDs), in which the brain and/or spinal cord of the fetus become irreversibly damaged, resulting in death before or shortly after birth, or handicap in surviving babies. Overall, NTDs occur in around 1 per 1,000 pregnancies although the rate varies and is significantly higher in some regions (e.g. Northern Ireland and Scotland). Worldwide, approximately 130,000 cases occur every year. The risk of NTDs depends on both inherited genetic factors and non-genetic factors such as diet, but the exact causes are not well understood. However, the risk of an affected pregnancy can be substantially reduced if the mother takes folic acid supplements before and during early pregnancy. Unfortunately, not all cases of NTDs are preventable by folic acid and for this reason, we are seeking additional protective approaches. Using a mouse model that naturally develops folate-resistant NTDs we found that another vitamin, inositol, can prevent NTDs, and we are now carrying out a clinical trial to test whether inositol prevents NTDs in humans. There are two main aims of the present research proposal. First, we will investigate the cause of the inositol-preventable NTDs in the mouse. We have used a technique that lets us separate many proteins and compare which ones are present in normal embryos and those that develop NTDs. We have detected several proteins that seem to be present at lower abundance or in abnormally modified forms in embryos developing NTDs. We will build on these studies by analysing the proteins that seem to be abnormal in the embryos that develop spina bifida. Understanding the role of specific proteins in the mouse may indicate risk factor genes in humans. The second aim of the research is to work out exactly how inositol prevents NTDs, as this may allow improvements to be made in the therapeutic approach. Knowledge of the causes of NTDs in humans may then allow more accurate counselling for affected families who are considering a further pregnancy, and may allow identification of women who will benefit from inositol supplementation.