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.

我们旨在了解甘氨酸脱羧酶（GLDC）蛋白的功能受损如何导致脑发育和功能的疾病。 GLDC的作用是分解一个称为甘氨酸的小分子，从而使一部分分子进入了称为叶酸代谢的化学反应网络，几乎所有细胞都需要用于许多不同功能。 GLDC活性的丧失，例如由于遗传基因突变而导致的，导致过量甘氨酸的积累和抑制叶酸代谢。我们的目标是了解这些变化如何导致出生前后出现的威胁生命的大脑疾病。这些疾病包括常见的先天缺陷，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4TOCOTION疾病非血糖高血糖（NKH）。异常的叶酸代谢有助于NTD，脑积水和NKH。理解因果关系也具有更广泛的相关性，因为叶酸代谢与其他疾病有关（例如，先天缺陷，癌症和神经系统疾病），并且可能会因遗传变化和其他因素（例如Diet.NTS）而改变，例如每1000次妊娠1-2个孕妇，由于后来的神经教育症状不足。胎儿的大脑和/或脊髓被不可逆转地损害，导致幸存儿童的出生或长期残疾死亡。由于可能有许多可能的因素，因此每个个体中NTD的确切原因通常是未知的。弄清GLDC缺陷如何导致NTDS提供了一个机会，可以更好地了解叶酸代谢和NTDS之间的联系。CongenitalHydrocephalus每1,000名婴儿影响0.5-1，并且由于大脑内脑脊髓流体的压力增加，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不正确的流体流量阻塞而引起的。导致当前研究的工作表明，这是叶酸代谢受损的结果。下一步是确切地了解何时及在哪个细胞中，大脑发育的过程出错，叶酸代谢的哪种输出受到破坏，以及这些变化是否负责脑积水。除了促进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，影响了每50,000名婴儿约1个，并导致癫痫病，深远的发育延迟和早期死亡。过量的甘氨酸和叶酸代谢对NKH的不同方面的相对贡献尚不很好，我们将解决这个问题。如果母亲在怀孕初期或怀孕期间服用补充叶酸（与叶酸有关）补充剂，则可以大大降低NTD的风险。但是，大量的NTD对叶酸具有抵抗力，需要鉴定其他疗法。关键目的是确定可以单独或与叶酸结合使用的NTD和脑积水的新预防疗法。在已经确定遗传危险因素的家庭中，这也意味着可以提供特定于家庭的疗法。当前对NKH治疗无效，无法治愈。为了实施新的疗法，重要的是要了解NKH的某些特征是否是由于异常出现在出生前已经显现出来的，以及是否可以纠正这些特征。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，Hydrocephalus和NKH基础机制的关键问题。这些模型提供了一个机会，可以确定GLDC缺陷对叶酸代谢和联系的生化反应的确切影响，这些反应如何导致前体细胞的变化对于大脑发育至关重要，以及特定的细胞在出生后大脑中是否异常。