Dietary intervention and mitochondrial toxicity in age-dependent model of glutari

戊二酸年龄依赖性模型中的饮食干预和线粒体毒性

• 批准号: 7665991
• 负责人: John M Flanagan
• 金额: $ 7.76万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665991
• 关键词: Academia; Adult; Affect; Age-Months; Amino Acids; Appearance; Astrocytes; Biochemical; Brain; Brain Injuries; Child; Child Care; Childhood; Citric Acid Cycle; Consumption; Corpus striatum structure; Development; Diagnostic tests; Diet; Dietary Intervention; Disease; Emotional; Employee Strikes; Encephalopathies; Enzymes; Failure; Fasting; Functional disorder; Glucose; Glutamates; Glutamine; Glutaryl-CoA dehydrogenase; Homoarginine; Human; Huntington Disease; Inborn Genetic Diseases; Injury; Knowledge; Lysine; Lysine Degradation Pathway; Measures; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolism; Mitochondria; Modeling; Molecular; Mus; Neurons; Oxidative Phosphorylation; Pathway interactions; Patients; Predisposition; Pyruvate Carboxylase; Research Personnel; Risk; Serum; Simulate; Testing; Time; Toxic effect; Translating; Tryptophan Metabolism Pathway; Wild Type Mouse; age related; antiport; cost; design; dietary supplements; effective therapy; feeding; glutaric acid; glutaric acidemia; improved; in vivo; injured; insight; mouse model; multidisciplinary; neurochemistry; neurotransmission; novel; prevent; public health relevance; saccharopine; therapy development; treatment strategy

DESCRIPTION (provided by applicant): Glutaryl-coenzyme A dehydrogenase (GCDH) deficiency is an inherited disorder of lysine and tryptophan metabolism known as glutaric acidemia type I (GA-I). Affected children develop striatal degeneration similar to Huntington's disease. However, the brain injury of GA-1 presents acutely during a period of susceptibility between 5 and 18 months of age and is commonly preceded by the catabolic state of illness or fasting. The mechanism of injury remains unknown. Current treatment consists of lysine restriction to limit glutaric acid producing substrate. Unfortunately, protection is incomplete and one-third of affected children develop striatal injuries regardless of treatment efforts. Tremendous financial and emotional costs are associated with caring for the children injured from GA-I, which may be a treatable disorder. In order to study the pathophysiology of GA-I and design better treatments, we developed a mouse model using GCDH-deficient (Gcdh-/-) mice exposed to increased dietary lysine that shows striking similarities to human GA-I. In this model, weanling but not adult Gcdh-/- mice accumulate substantial brain glutaric acid levels that correlate with severe brain injury. Age-dependent susceptibility in this model was shown to be associated with developmental differences in brain amino acid utilization. Brain injury in weanling but not adult mice was preceded by enhanced accumulation of lysine and then glutaric acid at the same time 1-ketoglutarate and glutamate were both depleted. Dietary intervention with atypical amino acid, homoarginine and glucose together was effective in reducing brain lysine and glutaric acid accumulation, which prevented injury in susceptible weanling Gcdh- /- mice. However, the use of homoarginine for human consumption poses a formidable regulatory challenge. Therefore, alternatives that have been determined safe for human use need to be identified and tested for potential treatment development. This is a proposal that brings together a multidisciplinary team to study the molecular mechanism of GA-I encephalopathy and use this information to identify safe, effective treatment strategies to prevent these striatal injuries. PUBLIC HEALTH RELEVANCE: This project represents an opportunity to develop protective treatments for glutaric aciduria that may be relevent to other childhood metabolic disorders.

描述（由申请人提供）：谷胱甘肽A脱氢酶（GCDH）缺乏症是一种赖氨酸和色氨酸代谢的遗传疾病，称为I型谷酸酸血症（GA-I）。受影响的儿童出现类似于亨廷顿氏病的纹状体变性。但是，GA-1的脑损伤在5至18个月大的易感性期间急性呈现，通常是疾病的分解代谢状态或禁食。损伤机制仍然未知。当前的治疗包括赖氨酸限制以限制谷氨酸产生底物。不幸的是，无论治疗工作如何，保护性不完整，三分之一的受影响儿童会造成纹状体伤害。巨大的财务和情感成本与照顾GA-I受伤的儿童有关，这可能是一种可治疗的疾病。为了研究GA-I和设计更好的治疗的病理生理学，我们使用了一种使用GCDH缺陷型（GCDH - / - ）小鼠开发了一种小鼠模型，暴露于增加的饮食赖氨酸，显示出与人类GA-I的惊人相似之处。在此模型中，断奶但不是成年GCDH - / - 小鼠积累了与严重脑损伤相关的大脑麸酸水平。在该模型中，年龄依赖性易感性与脑氨基酸利用率的发育差异有关。在断奶而不是成年小鼠的脑损伤之前，赖氨酸的积累增强，然后同时耗尽1-酮戊二酸酯和谷氨酸盐。与非典型氨基酸，同型精氨酸和葡萄糖一起饮食干预可有效减少脑赖氨酸和谷氨酸的积累，这阻止了易感性断奶的GCDH- / - 小鼠的损伤。但是，使用同性恋氨酸在人类消费中构成了巨大的监管挑战。因此，需要确定的人使用安全的替代方案需要识别和测试，以进行潜在的治疗开发。这是一项提议，汇集了一个多学科团队，以研究GA-1脑病的分子机制，并使用此信息来确定安全有效的治疗策略，以防止这些纹状体损伤。公共卫生相关性：该项目代表了开发可能与其他儿童代谢疾病有关的谷胱甘肽酸尿的保护性治疗的机会。