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型戊二酸血症（GA-I）。患病儿童会出现纹状体变性，类似于亨廷顿氏病。然而，GA-1的脑损伤在5 - 18个月大的易感期出现急性，通常在疾病或禁食的分解代谢状态之前出现。损伤的机制尚不清楚。目前的处理包括赖氨酸限制，以限制产生戊二酸的底物。不幸的是，保护是不完整的，无论治疗努力如何，三分之一的受影响儿童都会发生纹状体损伤。照顾因GA-I而受伤的儿童需要付出巨大的经济和情感成本，而GA-I可能是一种可治疗的疾病。为了研究GA-I的病理生理学和设计更好的治疗方法，我们开发了一个小鼠模型，使用Gcdh缺陷（Gcdh-/-）小鼠暴露于增加的饮食赖氨酸，显示出与人类GA-I惊人的相似性。在该模型中，断奶而非成年Gcdh-/-小鼠积累了大量与严重脑损伤相关的脑戊二酸水平。在这个模型中，年龄依赖性易感性被证明与大脑氨基酸利用的发育差异有关。断奶小鼠而非成年小鼠脑损伤发生前，赖氨酸和戊二酸积累增加，同时1-酮戊二酸和谷氨酸均耗尽。非典型氨基酸、同型精氨酸和葡萄糖联合干预能有效减少Gcdh- /-易感断奶小鼠脑赖氨酸和戊二酸的积累，从而预防损伤。然而，同型精氨酸用于人类消费构成了一个巨大的监管挑战。因此，需要确定对人类使用安全的替代品，并对其进行测试，以开发潜在的治疗方法。这是一个汇集多学科团队的建议，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：该项目为开发可能与其他儿童代谢紊乱相关的戊二酸尿的保护性治疗提供了机会。

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.