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The Glycine Cleavage System in Brain Development, Function and Disease

大脑发育、功能和疾病中的甘氨酸裂解系统

基本信息

批准号：
MR/W00500X/1
负责人：
Nicholas Greene
金额：
$ 299.24万
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：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW00500X%2F1
关键词：
Glycine Cleavage System Brain Development

项目摘要

We aim to understand how impaired function of the glycine decarboxylase (GLDC) protein leads to disorders of brain development and function. GLDC acts to break down a small molecule called glycine, allowing part of the molecule to enter a network of chemical reactions known as folate metabolism, which is needed in almost all cells for many different functions. Loss of GLDC activity, resulting for example from an inherited genetic mutation, leads to accumulation of excess glycine and to suppression of folate metabolism. Our goal is to understand how these changes lead to life-threatening brain diseases that arise both before and after birth. These disorders include common birth defects such as neural tube defects (NTDs) and congenital hydrocephalus, as well as the severe childhood disease Non-Ketotic Hyperglycinemia (NKH). Abnormal folate metabolism contributes to NTDs, hydrocephalus and NKH. Understanding causal links is also of broader relevance as folate metabolism is implicated in a range of other disorders (e.g. birth defects, cancers, and neurological disease), and may be altered by inherited genetic changes and other factors such as diet.NTDs occur in approximately 1-2 per 1,000 pregnancies, due to incomplete formation of the neural tube, which later develops into the brain and spinal cord. The brain and/or spinal cord of the fetus become irreversibly damaged, resulting in death around birth or long-term disability in surviving children. Because of the many possible contributory factors, the exact cause of NTDs in each individual is usually unknown. Working out how GLDC defects cause NTDs provides an opportunity to gain a better understanding of the link between folate metabolism and NTDs.Congenital hydrocephalus affects 0.5-1 per 1,000 babies and can lead to brain injury owing to increased pressure of cerebrospinal fluid within the brain. Hydrocephalus caused by GLDC mutation results from a blockage of fluid flow due to incorrect building of the fetal brain structure. Work leading to the current study shows that this is a result of impaired folate metabolism. The next step is to understand exactly when and in which cells the process of brain development goes wrong, which of the outputs of folate metabolism are disrupted, and whether these changes are responsible for hydrocephalus. In addition to contributing to NTDs and hydrocephalus, GLDC mutation is the major cause of NKH, an inherited disease that affects around 1 per 50,000 babies and causes epilepsy, profound development delay and early death. The relative contribution of excess glycine and impaired folate metabolism to different aspects of NKH is not well understood and we will address this question. The risk of NTDs can be substantially reduced if the mother takes supplemental folic acid (related to folate) supplements before or during early pregnancy. However, a substantial number of NTDs are resistant to folic acid and there is a need to identify additional therapies. A key aim is to identify new preventive therapies for NTDs and hydrocephalus which may be used individually or in combination with folic acid. In families where genetic risk factors have been identified this also means that family-specific therapies may be offered. Current treatments for NKH are not effective and there is no cure. In order to implement new therapies it is important to understand whether some features of NKH result from abnormalities that already manifest before birth and whether these can be corrected.We will address key outstanding questions about the mechanisms underlying NTDs, hydrocephalus and NKH using mouse and human cell models lacking function of GLDC. These models provide an opportunity to determine the precise effects of GLDC defects on folate metabolism and linked biochemical reactions, how these lead to changes in precursor cells that are essential for brain development and whether particular groups of cells are abnormal in the brain after birth.

我们的目的是了解甘氨酸脱羧酶（GLDC）蛋白功能受损如何导致大脑发育和功能障碍。GLDC的作用是分解一种名为甘氨酸的小分子，允许部分分子进入称为叶酸代谢的化学反应网络，这是几乎所有细胞中许多不同功能所必需的。GLDC活性的丧失，例如由遗传性基因突变引起，导致过量甘氨酸的积累和叶酸代谢的抑制。我们的目标是了解这些变化如何导致出生前后出现的危及生命的脑部疾病。这些疾病包括常见的出生缺陷，如神经管缺陷（NTD）和先天性脑积水，以及严重的儿童疾病非酮症高甘氨酸血症（NKH）。叶酸代谢异常导致NTD、脑积水和NKH。了解因果关系也具有更广泛的相关性，因为叶酸代谢与一系列其他疾病（例如出生缺陷，癌症和神经系统疾病）有关，并且可能会被遗传基因变化和其他因素（如饮食）改变。NTD发生在每1,000例妊娠中约1-2例，由于神经管形成不完全，随后发育成大脑和脊髓。胎儿的大脑和/或脊髓受到不可逆的损伤，导致出生前后死亡或存活儿童长期残疾。由于许多可能的促成因素，NTD在每个人的确切原因通常是未知的。了解GLDC缺陷如何导致NTDs提供了一个机会，以更好地了解叶酸代谢和NTDs之间的联系。先天性脑积水影响每1,000名婴儿中有0.5-1人，由于脑内脑脊液压力增加，可能导致脑损伤。由GLDC突变引起的脑积水是由于胎儿大脑结构的不正确构建导致的液体流动堵塞。导致目前研究的工作表明，这是叶酸代谢受损的结果。下一步是确切地了解大脑发育过程何时以及在哪些细胞中出错，叶酸代谢的哪些输出被破坏，以及这些变化是否是脑积水的原因。除了导致NTD和脑积水外，GLDC突变是NKH的主要原因，NKH是一种遗传性疾病，每50，000名婴儿中约有1名受到影响，并导致癫痫，严重发育迟缓和过早死亡。过量的甘氨酸和受损的叶酸代谢的不同方面的NKH的相对贡献还没有得到很好的理解，我们将解决这个问题。如果母亲在怀孕前或怀孕早期服用叶酸（与叶酸有关）补充剂，NTD的风险可以大大降低。然而，大量的NTD对叶酸具有耐药性，因此需要确定其他治疗方法。一个关键的目标是确定新的预防性治疗NTD和脑积水，可以单独使用或与叶酸联合使用。在已确定遗传风险因素的家庭中，这也意味着可以提供针对家庭的治疗。目前对NKH的治疗是无效的，也没有治愈的方法。为了实施新的治疗方法，重要的是要了解NKH的一些功能是否来自出生前已经表现出来的异常，以及这些是否可以纠正。我们将使用缺乏GLDC功能的小鼠和人类细胞模型来解决有关NTD，脑积水和NKH的机制的关键悬而未决的问题。这些模型提供了一个机会，以确定GLDC缺陷对叶酸代谢和相关生化反应的精确影响，这些如何导致对大脑发育至关重要的前体细胞的变化，以及出生后大脑中特定细胞群是否异常。