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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：
10745757
负责人：
Eric M Morrow
金额：
$ 3.26万
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/10745757
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

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.

项目总结