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.

我们的目标是了解甘氨酸脱羧酶（GLDC）蛋白的功能受损如何导致大脑发育和功能障碍。 GLDC 的作用是分解一种称为甘氨酸的小分子，使该分子的一部分进入称为叶酸代谢的化学反应网络，几乎所有细胞都需要叶酸代谢来实现许多不同的功能。例如由于遗传性基因突变而导致的 GLDC 活性丧失，会导致过量甘氨酸的积累并抑制叶酸代谢。我们的目标是了解这些变化如何导致出生前和出生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，例如神经管缺陷（NTD）和先天性脑积水，以及严重的儿童疾病非酮症高血糖症（NKH）。叶酸代谢异常会导致 NTD、脑积水和 NKH。了解因果关系也具有更广泛的意义，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，并且可能会因遗传性基因变化和饮食等其他因素而改变。NTD 的发生率约为每 1,000 次妊娠中就有 1-2 例出现这种情况，这是由于神经管（后来发育为大脑和脊髓）的形成不完整所致。胎儿的大脑和/或脊髓受到不可逆转的损伤，导致出生时死亡或幸存儿童长期残疾。由于可能的影响因素有很多，每个人患 NTD 的确切原因通常是未知的。弄清楚 GLDC 缺陷如何导致 NTD 为更好地了解叶酸代谢与 NTD 之间的联系提供了机会。每 1,000 名婴儿中就有 0.5-1 名患有先天性脑积水，并且由于大脑内脑脊液压力增加，可能导致脑损伤。 GLDC 突变引起的脑积水是由于胎儿大脑结构的错误构建导致液体流动受阻所致。目前的研究表明，这是叶酸代谢受损的结果。下一步是准确了解大脑发育过程何时以及在哪些细胞中出现问题，叶酸代谢的哪些输出被破坏，以及这些变化是否导致脑积水。除了导致 NTD 和脑积水之外，GLDC 突变还是 NKH 的主要原因，NKH 是一种遗传性疾病，影响大约每 50,000 名婴儿中就有 1 名，并导致癫痫、严重发育迟缓和过早死亡。过量甘氨酸和叶酸代谢受损对 NKH 不同方面的相对影响尚不清楚，我们将解决这个问题。如果母亲在怀孕前或怀孕期间补充叶酸（与叶酸相关），则可以大大降低患 NTD 的风险。然而，大量 NTD 对叶酸具有抗药性，因此需要确定其他疗法。一个关键目标是确定新的神经管缺陷和脑积水的预防疗法，这些疗法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 NKH 的治疗方法无效且无法治愈。为了实施新疗法，重要的是要了解 NKH 的某些特征是否是由出生前已经表现出来的异常引起的，以及这些特征是否可以纠正。我们将使用小鼠和人类来解决有关 NTD、脑积水和 NKH 潜在机制的关键悬而未决的问题缺乏GLDC功能的细胞模型。这些模型提供了一个机会来确定 GLDC 缺陷对叶酸代谢和相关生化反应的精确影响，这些影响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。