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.

项目摘要 我们最近发现 线粒体酶谷氨酸丙酮酸转氨酸酶2（GPT2）。遗传代谢疾病，例如GPT2 疾病，提供有力的镜头来研究人脑代谢机制。另外，代谢 疾病可能可以通过饮食限制或补充剂来治疗。 GPT2疾病涉及 大脑和进行性痉挛性截瘫的产后灌木丛。根据我们广泛的初步数据 我们已经建立了针对GPT2疾病的潜在治疗策略。为了指导儿童的干预措施， 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催化了可逆添加从谷氨酸到 丙酮酸，产生丙氨酸和A-酮戊二酸酯，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在神经元中起关键作用 通过调节神经丙氨酸的合成和无链球菌的生长。旋律（填充）是代谢 补充TCA循环中间体的过程。在高生物合成期间，孢子虫病很重要 需求，当消耗TCA循环中间体以合成大分子以用于细胞生长时， 被称为催化的过程。因此，此R01应用的核心目的是定义 GPT2介导的神经元发展和健康的机制，并研究机制的功效 基于治疗。 AIM 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 患者可见截瘫。在AIM1和AIM 2中，我们正在开发基于机制的救援策略 通过补充GPT2无效动物的饮食中的代谢产物来治疗运动缺陷。目标3意志 定义GPT2介导的代谢机制，用于体外神经元生长和治疗。这些 研究均在原发性小鼠神经元以及人类神经元（来自干细胞）中，以翻译 回到人类背景。我们有一个强大而多学科的团队，允许一个有力的 综合翻译方法，将面向患者的研究桥接到实验模型中。总之， 该提案中的研究将对基本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 疾病，目前尚无已知治疗。这一进展将为早期干预铺平道路，并 潜在地，预防GPT2疾病患者的神经系统损伤。最后，这些研究广泛 意义，因为我们将定义长期增长和健康所需的基本代谢机制 神经元，包括在多种神经疾病中易受伤害的长期注射运动神经元。