Mechanisms of disease and treatment in novel metabolic developmental brain disorders

新型代谢性发育性脑疾病的疾病机制和治疗

基本信息

批准号：
10375639
负责人：
Eric M Morrow
金额：
$ 57.86万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375639
关键词：
Affect Aging Alanine Amino Acids Animals Axon Back Brain Brain Diseases Child Childhood Citric Acid Cycle Clinical Trials Consumption Data Defect Development Diet Differentiation and Growth Disease Early Intervention Enzymes Essential Amino Acids Experimental Models Fostering Genetic Glutamates Growth Health Hindlimb Human Impairment In Vitro Intervention Knockout Mice Length Maintenance Mediating Metabolic Metabolic Diseases Metabolism Mitochondria Motor Motor Neurons Mus Mutation Nervous System Trauma Neuroglia Neurons Neurosciences Patients Phenotype Play Prevention Process Protein Biosynthesis Public Health Pyruvate Regulation Research Resources Role Spastic Paraplegia Supplementation Testing Therapeutic Therapeutic Effect Transaminases Translating alpha ketoglutarate amino group axon growth axonopathy base cancer cell cell growth deprivation dietary dietary restriction dietary supplements disability efficacy study human stem cells in vivo induced pluripotent stem cell innovation lens loss of function mutation macromolecule mitochondrial metabolism motor disorder multidisciplinary nervous system disorder neurogenetics neuron development neuronal growth novel null mutation patient oriented research postnatal pre-clinical preclinical study stem cells therapy development translational approach treatment strategy treatment trial

项目摘要

PROJECT SUMMARY We have recently identified a novel human neurogenetic disorder caused by loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). Genetic metabolic diseases, such as GPT2 disease, offer a powerful lens to investigate mechanisms of metabolism in human brain. Also, metabolic diseases may be amenable to treatments via dietary restrictions or supplements. GPT2 disease involves postnatal undergrowth of brain and progressive spastic paraplegia. Based on our extensive preliminary data, we have established potential treatment strategies for GPT2 disease. To guide these interventions in children, we propose to complete needed pre-clinical studies. GPT2 localizes to mitochondria and is upregulated during postnatal brain development. GPT2 catalyzes the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and a-ketoglutarate, a metabolite in the tricarboxylic acid (TCA) cycle. Our preliminary data provide support for disease mechanisms, wherein GPT2 plays a critical role in neuronal growth by regulating neuronal alanine synthesis and anaplerosis. Anaplerosis (filling-up) is the metabolic process whereby TCA cycle intermediates are replenished. Anaplerosis is important during high biosynthetic demand, when TCA cycle intermediates are consumed for synthesis of macromolecules for cell growth, a process known as cataplerosis. Therefore, the central objective of this R01 application is to define the role of GPT2-mediated mechanisms in neuronal development and health, and to study the efficacy of mechanism- based treatments. Aim 1 is focused on in vivo studies of Gpt2-mediated growth of motor neurons. Our Gpt2- null mouse recapitulates key aspects of disease, such as hindlimb motor abnormalities, akin to spastic paraplegia seen in patients. In Aim1 and in Aim 2, we are developing mechanism-based rescue strategies to treat motor defects in vivo through metabolite supplementation in the diets of Gpt2-null animals. Aim 3 will define GPT2-mediated metabolic mechanisms governing neuronal growth and treatments in vitro. These studies are in both primary mouse neurons, as well as in human neurons (from stem cells) in order to translate advances back to the human context. We have a strong and multidisciplinary team permitting a powerful integrated translational approach, bridging patient-oriented studies to experimental models. In summary, research in this proposal will have a sustained impact on both fundamental neuroscience and treatment development. We will evaluate therapeutic strategies that could be rapidly implemented in patients with GPT2 disease, which currently has no known treatment. This progress would pave the way for early intervention, and potentially, prevention of neurologic damage in patients with GPT2 disease. Finally, these studies have broad significance, as we will define basic metabolic mechanisms required for growth and health of long-projecting neurons, including long-projecting motor neurons that are vulnerable in a variety of neurological diseases.

项目概要我们最近发现了一种新的人类神经遗传性疾病，由基因功能丧失突变引起线粒体酶谷氨酸丙酮酸转氨酶 2 (GPT2)。遗传代谢疾病，例如GPT2 疾病，为研究人脑代谢机制提供了一个强大的镜头。另外，新陈代谢疾病可以通过饮食限制或补充剂来治疗。 GPT2疾病涉及产后脑部生长不足和进行性痉挛性截瘫。根据我们广泛的初步数据，我们已经制定了针对 GPT2 疾病的潜在治疗策略。为了指导儿童的这些干预措施，我们建议完成所需的临床前研究。 GPT2 定位于线粒体并在产后大脑发育。 GPT2 催化氨基从谷氨酸可逆加成丙酮酸，产生丙氨酸和α-酮戊二酸，这是三羧酸（TCA）循环中的代谢产物。我们的初步数据为疾病机制提供了支持，其中GPT2在神经元中发挥着关键作用通过调节神经元丙氨酸合成和回补来生长。回补（填充）是新陈代谢补充TCA循环中间体的过程。回补在高生物合成过程中很重要需求，当TCA循环中间体被消耗用于合成细胞生长的大分子时，称为猝倒症的过程。因此，此 R01 应用程序的中心目标是定义 GPT2介导的神经元发育和健康机制，并研究该机制的功效- 为基础的治疗。目标 1 专注于 Gpt2 介导的运动神经元生长的体内研究。我们的Gpt2- 无效小鼠概括了疾病的关键方面，例如后肢运动异常，类似于痉挛见于截瘫患者。在目标 1 和目标 2 中，我们正在制定基于机制的救援策略，以通过在 Gpt2 缺失动物的饮食中补充代谢物来治疗体内运动缺陷。目标3将定义 GPT2 介导的控制神经元生长和体外治疗的代谢机制。这些研究既针对原代小鼠神经元，也针对人类神经元（来自干细胞），以便将其转化为回到人类背景。我们拥有一支强大的跨学科团队综合转化方法，将以患者为导向的研究与实验模型联系起来。总之，该提案中的研究将对基础神经科学和治疗产生持续影响发展。我们将评估可在 GPT2 患者中快速实施的治疗策略疾病，目前尚无已知的治疗方法。这一进展将为早期干预铺平道路，并且潜在地预防 GPT2 疾病患者的神经损伤。最后，这些研究具有广泛的意义重大，因为我们将定义长期预测的生长和健康所需的基本代谢机制神经元，包括在各种神经系统疾病中易受影响的长突出运动神经元。