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

描述（由申请人提供）：戊二酰辅酶A脱氢酶（GCDH）缺乏症是一种遗传性赖氨酸和色氨酸代谢疾病，称为I型谷氨酸血症（GA-I）。受影响的儿童发生类似于亨廷顿病的纹状体变性。然而，GA-1的脑损伤在5至18个月大的易感期期间急性出现，并且通常在疾病或禁食的分解代谢状态之前。损伤机制尚不清楚。目前的治疗包括赖氨酸限制，以限制谷氨酸生产底物。不幸的是，保护是不完整的，三分之一的受影响的儿童发展纹状体损伤，无论治疗的努力。巨大的经济和情感成本与照顾GA-I受伤的儿童有关，GA-I可能是一种可治疗的疾病。为了研究GA-I的病理生理学并设计更好的治疗方法，我们使用暴露于增加的膳食赖氨酸的GCDH缺陷（Gcdh-/-）小鼠开发了一种小鼠模型，其显示出与人GA-I惊人的相似性。在该模型中，断奶而非成年Gcdh-/-小鼠积累了与严重脑损伤相关的大量脑谷氨酸水平。在该模型中，ESTA依赖的易感性被证明与脑氨基酸利用的发育差异有关。在断奶而非成年小鼠的脑损伤之前，赖氨酸和谷氨酸的积累增加，同时1-酮戊二酸和谷氨酸都被耗尽。饮食干预与非典型氨基酸，高精氨酸和葡萄糖一起有效地减少脑赖氨酸和谷氨酸的积累，从而防止在易感断奶Gcdh-/-小鼠的损伤。然而，高精氨酸用于人类消费带来了巨大的监管挑战。因此，需要确定和测试已被确定对人类安全使用的替代品，以开发潜在的治疗方法。这是一项汇集多学科团队的提案，旨在研究GA-I脑病的分子机制，并利用这些信息来确定安全，有效的治疗策略，以预防这些纹状体损伤。公共卫生相关性：该项目代表了开发戊二酸尿症保护性治疗方法的机会，该治疗方法可能与其他儿童代谢障碍相关。

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.