Mechanisms of Disease and Treatments in Novel Metabolic Development Brain Disorders

新型代谢发育脑疾病的疾病机制和治疗

• 批准号: 10622084
• 负责人: Eric M Morrow
• 金额: $ 2.8万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622084
• 关键词: Administrative Supplement; Award; Behavior; Biological Assay; Brain; Brain Diseases; Child; Data; Data Analyses; Development; Disease; Enzymes; Funding; Genetic; Glutamates; Growth; Health; Hindlimb; Histology; Human; Intervention; Knockout Mice; Laboratories; Learning; Mammalian Genetics; Manuscripts; Mediating; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Microscopy; Mitochondria; Motor; Motor Neurons; Nerve Degeneration; Neurons; Patients; Phase; Preparation; Public Health; Pyruvate; Research; Research Assistant; Research Training; Science; Spastic Paraplegia; Techniques; Training; Transaminases; Underrepresented Populations; United States National Institutes of Health; Universities; Work; base; career; career development; dietary restriction; dietary supplements; experience; in vivo; interest; lens; loss of function mutation; motor behavior; nervous system disorder; neurodevelopment; neurogenetics; novel; parent grant; postnatal; preclinical study; programs; symposium; treatment strategy

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 are currently completing needed pre-clinical studies under the awarded parent grant “Mechanisms of disease and treatment in novel metabolic developmental brain disorders 1R01NS121618-01A1”. This application represents a request for supplemental funding to support the post-baccalaureate training of Mr. Kenneth Bradley. Mr. Bradley is a recent Brown University graduate and will be a research assistant working on projects under the scope of the parent grant within the Morrow Laboratory. Mr. Bradley will work primarily on training and conducting studies related to Aim 1 of this project, since Mr. Bradley is specifically interested in neurogenetics and motor behavior in neurodevelopmental and neurodegenerative conditions. 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. This supplement outlines research and training plans that will build-upon Mr. Bradley’s existing skillset, and that will dovetail with his scientific interests going forward. In addition to learning mammalian genetics, neurodevelopment and the laboratory techniques of histology, microscopy and behavior assays, Mr. Bradley will be provided with a mentorship on career development from multiple mentors and supervisors, will attend a conference, and receive training in data analysis and manuscript preparation. Taken together, these experiences will assist Mr. Bradley as he prepares for the next phase of his career in the biomedical workforce. Page 41 of 55

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。为了指导儿童的这些干预措施，我们 目前，是否正在根据授予的父母授予的“疾病机制”完成所需的临床前研究 和新型代谢发育性脑疾病的治疗1R01NS121618-01A1。 代表了补充资金的请求，以支持肯尼斯·布拉德利先生的学士后培训。 布拉德利先生是最近的布朗大学毕业生，将是一名研究助理 Morrow实验室内的父母赠款范围。布拉德利先生将主要从事培训和 进行与该项目目标1相关的研究，因为布拉德利先生对神经源特别感兴趣 以及神经发育和神经退行性条件的运动行为。 AIM 1专注于体内 GPT2介导的运动神经元生长的研究。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，类似于患者的痉挛性截瘫。这种补充概述了 研究和培训计划将建立布拉德利先生的现有技能，这将与他的 科学利益将来。除了学习哺乳动物遗传学，神经发育和 组织学，显微镜和行为分析的实验室技术，将为布拉德利先生提供 多个导师和主管的职业发展指导，将参加会议，并接受 数据分析和手稿准备方面的培训。综上所述，这些经历将帮助布拉德利先生 当他为生物医学劳动力的下一阶段做准备时。 第41页，共55页