THERAPEUTIC AND STABLE ISOTOPIC INVESTIGATION OF THE UREA CYCLE DISORDERS

尿素循环障碍的治疗性和稳定同位素研究

• 批准号: 8166658
• 负责人: Brendan Lee
• 金额: $ 14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166658
• 关键词: Acetylation; Acids; Adult; Amino Acids; Ammonia; Anorexia; Arginine; Argininosuccinate lyase deficiency; Argininosuccinic Acid; Brain; Carbamyl Phosphate; Catabolism; Cessation of life; Child; Childhood; Cirrhosis; Citrulline; Citrullinemia; Clinic; Coma; Computer Retrieval of Information on Scientific Projects Database; Diet; Dietary intake; Disease; Dose; Enzymes; Etiology; Excretory function; FDA approved; Fibrosis; Frequencies; Fumarates; Funding; Glutamine; Grant; Health; Hepatic; Hepatomegaly; Heterogeneity; Histology; Human Genetics; Hyperammonemia; Hyperargininemia; Impairment; Incidence; Infection; Inflammation; Institution; Investigation; Lead; Life; Ligase; Live Birth; Liver; Liver Fibrosis; Lyase; Magnetic Resonance Imaging; Measures; Medical; Metabolic; Methods; Minor; Mutation; Neonatal; Neurologic; Nitrogen; Ornithine carbamoyltransferase deficiency; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenylacetates; Phenylbutyrates; Production; Protein-Restricted Diet; Proteins; Reaction; Recrudescences; Renal clearance function; Reproduction; Research; Research Personnel; Resources; Severities; Sodium phenylbutyrate; Source; Supplementation; Symptoms; Therapeutic; Time; Transaminases; United States National Institutes of Health; Urea; Urine; Vomiting; Water; arginine treatment; argininosuccinate lyase; base; infancy; liver biopsy; liver transplantation; neonate; nitrogen compounds; urea cycle; urinary

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The urea cycle is required for excretion of excess nitrogen compounds generated by dietary intake and protein catabolism (1). Human genetic deficiencies of urea cycle enzymes are well known and usually present in the neonatal period or early infancy with metabolic crises and subsequent neurological impairment. Each disease has significant variability in severity. The most common urea cycle disorder is ornithine transcarbamylase (OTC) deficiency. The other urea cycle disorders are carbamyl phosphate synthetase (CPS), argininosuccinic acid synthetase (ASS), argininosuccinate lyase (ASL), and arginase deficiencies. Argininosuccinic acide lyase defiency is also known as Argininosuccinic aciduria (ASA). ASA has an incidence of one in seventy thousand live births and commonly presents in the neonatal period with hyperammonemic metabolic crisis. The clinic picture is that of a healthy appearing neonate who, after a short period of health, develops vomiting, lethargy and anorexia. These symptoms rapidly progress to coma and death if not treated. If the hyperammonemia is prolonged, there is severe and permanent neurolgical impairment. "Neonatal rescue" by heodialysis and alternative pathway drugs is typically followed by life long episodic hyperammonemia usually precipitated by minor infections or dietary imbalance. Recrudescence of hyperammonemia leads to further neurological injury2. Less severe forms of ASA and other urea cyc cycle disorders may present during infancy, childhood, or adulthood and are a consequence of mutation heterogeneity. Treatment of urea cycle disorders relies on two strategies(2,3). The first is reproduction of nitrogen load through the use of a protein-restricted diet. The second approach uses "alternate" or laten enzymatic pathways of the liver to conjugate amino acids to carrier molecules (exogenously administered drugs) and arginine supplementation to increase urinary excretion of nitrogenous products. Currently, ASA patients are treated only with diet and arginine therapy. The principle of arginine therapy is that by replacing the product of downstream of the impaired reaction in the urea cycle (argininosuccinic acid is converted to arginine and fumarate by argininosuccinic acid lyase); the cycle is "reprimed" to continue to produce additional argininosuccinic acid. Because of its extremely high renal clearance, it acts effectively as an efficient nitrogen sink in place of urea. A FDA approved therapy for other disorders earlier in the urea cycle, i.e., ornithine transcarbamylase deficiency and citrullinemia, is sodium phenylbutyrate (Buphenyl). At present there is little quantitative information as to the specific effect of sodium phenylbutyrate on the ability to reduce frequency of hyperammonemic crisis, hepatic transaminase levels, and citrulline/argininosuccinate levels in ASA. Sodium phenylbutyrate is rapidly converted to phenylacetate after administration. Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine. This compound is water-soluble and is then excreted in the urine. In this way, phenylbutyrate serves as an alternative vehicle for nitrogen excretion. Marked hepatomegaly is a hallmark of ASA and is not found to such a degree in the other urea cycle disorders. Hepatic fibrosis has been documented by liver biopsy of these patients and generally begins early in the disease (4,5). The majority of these patients also have elevations of hepatic transaminases (ALT and AST) to > 2x normal levels. The etiology of these elevations is not known but it has been shown that they occur independently of ammonia control. It is probable that the degree of liver fibrosis correlates to transaminase levels. As children with this disorder survive for longer periods of time with better methods of medical management, it will become more important to better control transaminase levels to avoid fibrosis, which may lead to life threatening cirrhosis. Liver transplantation has been performed in cases of severe cirrhosis. Since the unique metabolite in this condition is arininosuccinic acid and/or its breakdown products, we hypothesize that argininosuccinic acid and/or its metabolites may be the offending agent causing hepatic inflammation. Ironically, the current therapy of high dose arginine treatment is aimed at effectively decreases the frequency of hyperammonemia, hence protecting the brain, it may increase the occurrence of hepatic inflammation. Based on these observations, we hypothesize that by stimulating alternative disposal of nitrogen by diverting nitrogen flux away from the production of argininosuccinic acid, we may observe decreased hepatic inflammation as evidence by decreased LFT s, stabilization or improvement of hepatic fibrosis as measured by MRI and histology where clinically available. Moreover, we may also observe a greater tolerance for dietary peripheral nitrogen and hence decrease the frequency and magnitude of hyperammonemia and decreased steady state level of ASA.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 尿素循环是排泄饮食摄入和蛋白质催化剂产生的过量氮化合物所必需的（1）。尿素循环酶的人类遗传缺陷是众所周知的，通常存在于新生儿期或婴儿早期，伴有代谢危象和随后的神经损伤。每种疾病的严重程度都有很大的差异。最常见的尿素循环障碍是鸟氨酸转氨甲酰酶（OTC）缺乏症。其他尿素循环障碍是氨甲酰磷酸合成酶（CPS）、氨基琥珀酸合成酶（ASS）、氨基琥珀酸裂解酶（ASL）和氨基琥珀酸酶缺乏。精氨酸琥珀酸裂解酶缺乏症也称为精氨酸琥珀酸尿症（阿萨）。 阿萨的发病率为七万分之一，通常在新生儿期出现高血氨代谢危象。临床图片是一个看起来健康的新生儿，在短时间的健康之后，出现呕吐、嗜睡和厌食。如果不治疗，这些症状会迅速发展为昏迷和死亡。如果高氨血症持续时间长，则会出现严重和永久性的神经功能损害。通过血液透析和替代途径药物进行的“新生儿抢救”通常会导致终身发作性高氨血症，通常由轻微感染或饮食失衡引起。高氨血症的复发导致进一步的神经损伤2。轻度阿萨和其他尿素循环 周期紊乱可在婴儿期、儿童期或成年期出现，并且是突变异质性的结果。 尿素循环障碍的治疗依赖于两种策略（2，3）。第一个是通过使用蛋白质限制饮食来复制氮负荷。第二种方法使用肝脏的“替代”或潜伏酶途径将氨基酸缀合至载体分子（外源性施用的药物）并补充精氨酸以增加含氮产物的尿排泄。目前，阿萨患者仅接受饮食和精氨酸治疗。精氨酸治疗的原理是通过替换尿素循环中受损反应下游的产物（氨基琥珀酸通过氨基琥珀酸裂解酶转化为精氨酸和富马酸盐）;该循环被“重新启动”以继续产生额外的氨基琥珀酸。由于其极高的肾脏清除率，它有效地作为一个有效的氮库，而不是尿素。 FDA批准的用于尿素循环早期其他疾病的治疗，即，鸟氨酸转氨甲酰酶缺乏症和瓜氨酸血症，是苯丁酸钠（Buphenyl）。目前，关于苯丁酸钠降低阿萨患者高血氨危象频率、肝转氨酶水平和瓜氨酸/氨基琥珀酸水平的能力的特异性作用的定量信息很少。苯丁酸钠在给药后迅速转化为苯乙酸。苯乙酸盐是一种代谢活性化合物，通过乙酰化作用与谷氨酰胺结合形成苯乙酰谷氨酰胺。这种化合物是水溶性的，然后通过尿液排出。以这种方式，苯丁酸酯作为氮排泄的替代载体。 显著肝肿大是阿萨的标志，在其他尿素循环障碍中未发现这种程度。这些患者的肝活检记录了肝纤维化，通常在疾病早期开始（4，5）。这些患者中的大多数还具有肝转氨酶（ALT和AST）升高至> 2倍正常水平。这些升高的病因尚不清楚，但已表明它们的发生与氨控制无关。肝纤维化的程度可能与转氨酶水平有关。随着患有这种疾病的儿童通过更好的医疗管理方法存活更长时间，更好地控制转氨酶水平以避免纤维化将变得更加重要，纤维化可能导致危及生命的肝硬化。严重肝硬化的病例已经进行了肝移植。由于在这种情况下的独特代谢产物是arininosuccinic酸和/或其分解产物，我们假设arinosuccinic酸和/或其代谢产物可能是引起肝脏炎症的致病因子。具有讽刺意味的是，目前高剂量精氨酸治疗的目的是有效降低高氨血症的频率，从而保护大脑，它可能会增加肝脏炎症的发生。基于这些观察结果，我们假设，通过将氮通量从氨基琥珀酸的生产中转移出来，刺激氮的替代处置，我们可以观察到肝脏炎症减少，如通过MRI和组织学（临床可用）测量的LFT减少、肝纤维化稳定或改善所证明。此外，我们还可以观察到对饮食外周氮的更大耐受性，从而降低高氨血症的频率和程度，并降低阿萨的稳态水平。