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: 7950594
• 负责人: Brendan Lee
• 金额: $ 2.07万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950594
• 关键词: Acetylation; Acids; Amino Acids; Ammonia; Anorexia; Arginine; Argininosuccinate lyase deficiency; Argininosuccinic Acid; Brain; Carbamyl Phosphate; Catabolism; Cessation of life; Child; Childhood; Cirrhosis; Citrulline; Citrullinemia; Clinic; Clinical Research; 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; Research; Research Personnel; Resources; Severities; Sodium phenylbutyrate; Source; Supplementation; Symptoms; Therapeutic; Time; Transaminases; United States National Institutes of Health; Urea; Urine; Vomiting; Water; abstracting; 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. ABSTRACT The urea cycle is required for excretion of excess nitrogen compounds generated by dietary intake and protein catabolism. 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 deficiency. The other urea cycle disorders are carbamyl phosphate synthetaseargininosuccinic acid synthetase, argininosuccinate lyase, and arginase deficiencies. Argininosuccinic acide lyase defiency is also known as Argininosuccinic aciduria. 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 peiord 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 cyccle disorders may present during infancy, childhood, or adulthood and are a consequence of mutation heterogeneity. Treatment of urea cycle disorders relies on two strategies. The first is reductioon 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. 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 抽象的 尿素周期是由饮食摄入和蛋白质分解代谢产生的过量氮化合物排泄所必需的。尿素周期酶的人类遗传缺陷是众所周知的，通常存在于新生儿时期或婴儿期出现代谢危机以及随后的神经系统障碍。每种疾病的严重程度有显着差异。最常见的尿素循环障碍是鸟氨酸经钙化酶缺乏症。其他尿素循环疾病是磷酸磷酸磷酸合成蛋白核酸合成酸合成酶，精氨酸糖酸酯裂解酶和精氨酸酶缺乏症。精氨酸糖苷酶裂解酶的缺乏症也称为精氨酸酸性酸尿。 ASA的发生率是七万万活出生，通常在新生儿时期出现高ammon血症代谢危机。诊所的情况是一个健康的新生儿的诊所，他的健康状况不足后会发展出呕吐，嗜睡和厌食症。这些症状迅速发展为昏迷和死亡，如果没有治疗。如果高症血症延长，则会存在严重且永久性的神经性障碍。 Heodiaysis和替代途径药物的“新生儿救援”通常是寿命长的发作性高症血症，通常是由于轻微感染或饮食失衡而导致的。高症血症的复发导致进一步的神经损伤2。在婴儿期，儿童期或成年期可能存在的ASA和其他尿素Cyccle疾病的严重形式不太严重，这是突变异质性的结果。 尿素周期疾病的治疗取决于两种策略。首先是通过使用蛋白质限制饮食来减少氮负荷。第二种方法使用肝脏的“替代”或拉丁酶途径将氨基酸与外源施用的药物和精氨酸补充剂结合到载体分子中，以增加硝基产物的尿液排泄。目前，ASA患者仅接受饮食和精氨酸治疗。精氨酸疗法的原理是，通过在尿素周期中替换受损反应下游的产物（通过精氨酸糖酸裂解酶转化为精氨酸和富马酸），循环“谴责”以继续产生其他精氨酸糖酸。由于其极高的肾脏清除率，它有效地充当有效的氮气下沉，代替了尿素。 FDA在尿素周期较早的其他疾病的批准治疗，即鸟氨酸经钙化酶缺乏症和瓜氨酸血症，是苯基丁酸钠（buphenyl）。目前，几乎没有关于苯丁酸钠对降低高症危机频率，肝转氨酸酶水平以及瓜氨酸/精氨酸偶联水平的特定作用的数量信息。给药后，将苯基丁酸钠迅速转化为苯乙酸酯。苯乙酸酯是一种代谢活性化合物，通过乙酰化与谷氨酰胺结合形成苯乙酰谷氨酰胺。该化合物是水溶性的，然后在尿液中排出。这样，苯丁酸酯是氮排泄的替代载体。 标记的肝肿大是ASA的标志，在其他尿素周期疾病中没有找到这样的学位。肝纤维化已通过这些患者的肝活检记录，通常在疾病的早期开始。这些患者中的大多数还升高肝转氨酶（ALT和AST）至正常水平> 2倍。这些海拔的病因尚不清楚，但已表明它们独立于氨控制。肝纤维化程度可能与转氨酶水平相关。随着患有这种疾病的儿童以更好的医疗管理方法生存更长的时间，更好地控制跨激酶水平以避免纤维化将变得越来越重要，这可能导致威胁生命的肝硬化。在严重肝硬化的情况下，已经进行了肝移植。由于在这种条件下的独特代谢产物是芳烯烯糖糖酸和/或其分解产物，因此我们假设精氨酸糖酸和/或其代谢物可能是引起肝炎症的有害剂。具有讽刺意味的是，当前的高剂量精氨酸治疗方法旨在有效降低高症血症的频率，因此保护大脑，可能会增加肝炎的发生。基于这些观察结果，我们假设，通过将氮通量从产生的氮气中刺激氮的替代处置，我们可能会通过降低LFT，稳定性或改善肝纤维化的方法来观察到肝炎症的降低，这是通过MRI和HISTOLOGY培训的术语来降低的。此外，我们还可以观察到对饮食外周氮的耐受性，从而降低了高氨血症的频率和幅度，并降低了ASA的稳态水平。