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

肌醇可预防的神经管缺陷：了解分子原因和预防机制

• 批准号: G0601546/1
• 负责人: Nicholas Greene
• 金额: $ 76.94万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0601546%2F1
• 关键词: Inositol; preventable; neural; tube; defects

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.

在怀孕初期，发育中的胚胎中的一个关键事件是神经管的形成，后来将发展为大脑和脊髓。神经管正确形成的失败会导致一组出生缺陷，称为神经管缺陷（NTDS），其中胎儿的大脑和/或胎儿的大脑和/或脊髓会受到不可逆转的损害，导致出生前或出生后不久或生存婴儿中的残障。总体而言，NTD发生在每1000次妊娠约1个，尽管率有所不同，并且在某些地区（例如北爱尔兰和苏格兰）也有明显更高。在全球范围内，每年发生大约13万例病例。 NTD的风险取决于遗传因素和非遗传因素（例如饮食），但确切的原因尚不清楚。但是，如果母亲在怀孕前后服用叶酸补充剂，则可能会大大降低患妊娠的风险。不幸的是，并非所有NTD的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。使用自然发展抗叶酸NTD的小鼠模型，我们发现另一种维生素肌醇可以预防NTD，并且我们现在正在进行临床试验以测试肌醇是否可以阻止人类的NTDS。本研究计划有两个主要目的。首先，我们将研究小鼠中可预除肌醇的NTD的原因。我们使用了一种使我们可以分开许多蛋白质的技术，并比较了哪些蛋白质在正常胚胎和发展NTD的蛋白质中存在。我们已经检测到几种蛋白质似乎存在于较低的丰度或发育中的胚胎中的异常修饰形式。我们将通过分析在发展脊柱裂的胚胎中似乎异常的蛋白质来基于这些研究。了解特定蛋白在小鼠中的作用可能表明人类中的危险因素基因。该研究的第二个目的是准确弄清肌醇如何阻止NTD，因为这可以使治疗方法改进。然后，了解人类NTD的原因可能会为正在考虑进一步怀孕的受影响家庭提供更准确的咨询，并且可以识别将从补充肌醇中受益的妇女。