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强大的视角。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 已经建立了 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 目前正在根据授予的家长补助金“疾病机制”完成所需的临床前研究 新型代谢性发育性脑部疾病的治疗和治疗 1R01NS121618-01A1”。该申请 代表请求补充资金以支持 Kenneth Bradley 先生的学士学位后培训。 布拉德利先生是布朗大学应届毕业生，将担任研究助理，负责该项目的项目 莫罗实验室内家长资助的范围。布拉德利先生将主要从事培训和 由于 Bradley 先生对神经遗传学特别感兴趣，因此正在进行与该项目目标 1 相关的研究 以及神经发育和神经退行性疾病中的运动行为。目标1专注于体内 Gpt2 介导的运动神经元生长的研究。我们的 Gpt2 缺失小鼠概括了疾病的关键方面， 例如后肢运动异常，类似于患者中看到的痉挛性截瘫。本补充概述 研究和培训计划将建立在布拉德利先生现有的技能基础上，并且与他的能力相吻合 科学兴趣的发展。除了学习哺乳动物遗传学、神经发育和 组织学、显微镜检查和行为分析的实验室技术，布拉德利先生将获得 来自多位导师和主管的职业发展指导，将参加会议，并获得 数据分析和稿件准备方面的培训。总而言之，这些经验将对布拉德利先生有所帮助 当他为生物医学工作者职业生涯的下一阶段做准备时。 第 41 页，共 55 页