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

描述(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障碍，称为戊二酸I型(GA-I)。受影响的儿童会患上类似亨廷顿氏病的纹状体变性。然而，GA-1的脑损伤在5至18个月龄的敏感期出现，通常在疾病或禁食的分解代谢状态之前出现。受伤机制尚不清楚。目前的治疗包括限制赖氨酸，以限制产生戊二酸的底物。不幸的是，保护是不完整的，三分之一的受影响儿童不顾治疗努力而发生纹状体损伤。巨大的经济和情感成本与照顾因GA-I受伤的儿童有关，GA-I可能是一种可以治疗的疾病。为了研究GA-I的病理生理学，并设计更好的治疗方法，我们利用GCDH缺陷(Gcdh-/-)小鼠建立了一种小鼠模型，暴露于与人类GA-I惊人相似的饮食赖氨酸。在这个模型中，断奶的Gcdh-/-小鼠而不是成年的Gcdh-/-小鼠积累了大量的脑组织戊二酸水平，这与严重的脑损伤有关。在这个模型中，年龄相关的易感性被证明与大脑氨基酸利用的发育差异有关。在断奶小鼠而不是成年小鼠的脑损伤之前，赖氨酸和戊二酸的积累增加，同时1-酮戊二酸和谷氨酸都被耗尽。联合使用非典型氨基酸、高精氨酸和葡萄糖的饮食干预能有效地减少脑内赖氨酸和戊二酸的积累，从而预防易感断奶Gcdh-/-小鼠的损伤。然而，将高精氨酸用于人类消费构成了一个艰巨的监管挑战。因此，需要确定对人类使用安全的替代品，并对潜在的治疗开发进行测试。这项建议汇集了一个多学科团队来研究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，以防止这些纹状体损伤。公共卫生相关性：该项目提供了一个机会，可以开发可能与其他儿童代谢紊乱有关的戊二酸尿症的保护性治疗方法。

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.