Grainyhead-like genes and mammalian neural tube defects

粒头样基因和哺乳动物神经管缺陷

• 批准号: G0802163/1
• 负责人: Nicholas Greene
• 金额: $ 80.26万
• 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: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0802163%2F1
• 关键词: Grainyhead; like; genes; mammalian; neural

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. We are studying mouse strains that are predisposed to develop NTDs that resemble the corresponding human birth defects, with the aim of understanding why the defects develop and finding ways to prevent them. In one of these strains, curly tail, we found that reduced expression of a gene called grainyhead-like-3, causes NTDs. We now have evidence to suggest that increased expression of the same gene or a related gene, grainyhead-like-2, can also cause NTDs, and we propose to use genetic approaches to test this idea. We will then investigate how the altered expression of the grainyhead-like genes changes cellular behaviours and thereby alters the mechanical properties of the developing embryo such that the neural tube fails to close. Finally, we will test whether dysregulation of grainyhead-like-2 and -3 cause NTDs through similar or differing effects on the expression of other ?downstream? genes. Identification of the genes that cause NTDs in mice may indicate genes that may be causative in humans. Knowledge of the genes responsible for NTDs in humans may then allow more accurate counselling for affected families who are considering a further pregnancy, and may allow development of novel therapeutic strategies.

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。我们正在研究易于发展类似于人类出生缺陷的NTD的小鼠菌株，目的是理解为什么缺陷会发展并找到防止它们的方法。在这些菌株之一，卷曲的尾巴中，我们发现降低了称为粒状头样3的基因的表达会导致NTD。现在，我们有证据表明，同一基因或相关基因类似颗粒状的基因-2的表达增加也可能引起NTD，我们建议使用遗传方法来测试这一想法。然后，我们将研究类似颗粒状基因的表达改变的表达如何改变细胞行为，从而改变发育中的胚胎的机械性能，从而使神经管无法关闭。最后，我们将测试粒状头样-2和-3的失调是否通过对其他？下游表达的相似或不同的影响引起NTD？基因。在小鼠中引起NTD的基因的鉴定可能表明人类可能是致病性的基因。然后，了解人类NTD的基因的知识可能会为正在考虑进一步怀孕的受影响家庭的受影响家庭提供更准确的咨询，并且可能允许发展新型的治疗策略。