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

• 批准号: 10527375
• 负责人: Eric M Morrow
• 金额: $ 58.01万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 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/10527375
• 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; 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; Neuronal Differentiation; 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; 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

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.

项目总结 我们最近发现了一种新的人类神经遗传学疾病，由功能丧失突变引起 线粒体酶谷丙转氨酶2(GPT2)。遗传性代谢性疾病，如GPT2 疾病，为研究人类大脑的新陈代谢机制提供了一个强大的透镜。此外，新陈代谢 疾病可以通过饮食限制或补充剂进行治疗。GPT2疾病涉及 出生后脑发育不足和进行性痉挛截瘫。根据我们广泛的初步数据， 我们已经为GPT2疾病制定了潜在的治疗策略。为了指导对儿童的这些干预， 我们建议完成所需的临床前研究。GPT2定位于线粒体，并在 出生后大脑发育。GPT2催化谷氨酸到谷氨酸的氨基可逆加成 丙酮酸，产生丙氨酸和a-酮戊二酸，三羧酸(TCA)循环中的代谢物。我们的 初步数据为疾病机制提供了支持，其中GPT2在神经元中发挥关键作用 通过调节神经元丙氨酸的合成和失活而生长。Anaplerosis(填满)是新陈代谢 补充三氯乙烷循环中间体的过程。在高生物合成过程中，回旋作用是重要的 需求，当TCA循环中间体被消耗来合成用于细胞生长的大分子时， 这一过程被称为瀑布效应。因此，此R01应用程序的中心目标是定义 GPT2介导的机制在神经元发育和健康中的作用，并研究机制- 以治疗为基础。目的1主要研究Gpt2介导的运动神经元生长的体内研究。我们的Gpt2- Null小鼠概括了疾病的关键方面，如后肢运动异常，类似于痉挛 病人出现截瘫。在Aim1和Aim 2中，我们正在制定基于机制的救援战略，以 通过在Gpt2缺失动物的日粮中补充代谢物来治疗体内的运动缺陷。目标3将 明确GPT2介导的代谢机制在体外控制神经元生长和治疗。这些 研究既在原代小鼠神经元上进行，也在人类神经元(来自干细胞)上进行，以便翻译 回到人类的背景下。我们有一支强大的多学科团队，允许一支强大的 综合转换方法，将以患者为中心的研究与实验模型联系起来。总而言之， 这项提议的研究将对基础神经科学和治疗产生持续的影响 发展。我们将评估可以在GPT2患者中迅速实施的治疗策略 目前还没有已知的治疗方法。这一进展将为早期干预铺平道路， 潜在地，预防GPT2病患者的神经损害。最后，这些研究具有广泛的意义 意义，因为我们将定义生长和健康所需的基本代谢机制 神经元，包括长时间投射的运动神经元，在各种神经疾病中都很脆弱。