Extreme Ammonia Tolerance Mechanisms: A Model Vertebrate

极端氨耐受机制：脊椎动物模型

• 批准号: 6684175
• 负责人: Patrick Joseph Walsh
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF MIAMI ROSENTEIL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-08 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684175
• 关键词: ammonia; astrocytes; biomarker; brain metabolism; detoxification; disease /disorder model; environmental toxicology; enzyme activity; glutamate ammonia ligase; hepatic coma /encephalopathy; hippocampus; immunocytochemistry; laboratory rat; mitochondria; model design /development; neural degeneration; neurochemistry; neuroprotectants; neurotoxicology; nicotinamide adenine dinucleotide; poisoning; sulfur aminoacid; tertiary amine; tissue /cell culture; toad; western blottings

DESCRIPTION (provided by applicant): Hepatic Encephalopathy (HE), and resultant elevated blood and tissue ammonia concentrations (i.e., hyperammonemia, HA), has profound central nervous system (CNS) effects, and can have environmental causes. In particular, liver damage due to exposure to toxicants such as carbon tetrachloride, toluene, DDT, heptachlor, etc., as well as chronic alcoholism and direct exposure to environmental ammonia, can elicit symptoms of HE/HA. However, there are such a wide variety of CNS effects produced in the disease in humans, and in rodent experimental models, that it is difficult to determine which disease biomarkers are the most critical indicators of disease progression. Furthermore, characteristics of the rodent model present several weaknesses in the study of HE/HA. Because of this gap in our knowledge, no practical and effective clinical intervention strategies are available to prevent or reverse biomarkers or symptoms of the disease. Recently, we have identified a vertebrate model, the gulf toadfish (Opsanus beta), which is both extremely tolerant of ammonia insult, and which, by virtue of its aquatic lifestyle, enables a line of experimentation not practical in mammalian models, namely rapid "ammonia washout" protocols. Therefore, we propose to test several hypotheses aimed at exploiting these and other characteristics of this new model to address the lack of biomarkers and intervention strategies for HE/HA. In particular, we will: (1) test the hypothesis that there are reversible vs. irreversible biomarkers of HE/HA, and that these can be readily identified and distinguished in an aquatic model like the toadfish; (2) test the hypotheses that extreme ammonia tolerance in the toadfish, relative to mammals, is due to an unusual aspect of its physiology, in particular, either to a more robust ammonia detoxification system in the brain, or to an inherent insensitivity of brain mitochondrial metabolism to ammonia insult. As a further test of this second hypothesis, we will also explore the possibility that the toadfish has higher levels of naturally occurring ammonia protectant compounds (e.g., carnitine, trimethylamine oxide, etc.) in its brain tissues than do mammals. In sum, these experiments will lead to information which is not readily obtainable from humans and existing mammalian models concerning the mechanisms of action of ammonia and cellular capacity for tolerance and recovery, and thus to a better understanding of the causes and mechanisms underlying HE/HA that could lead to therapeutic strategies.

描述（由申请人提供）：肝性脑病（HE），并结果 血液和组织氨浓度升高（即高症血症，HA）， 具有深刻的中枢神经系统（CNS）效应，并且可以具有环境 原因。特别是，由于暴露于碳等有毒物质而造成的肝脏损害 四氯化物，甲苯，滴滴涕，七烯酸等以及慢性酒精中毒 直接暴露于环境氨中，可以引起HE/HA的症状。 但是，该疾病中产生了多种CNS效应 在人类和啮齿动物实验模型中，很难确定 哪些疾病生物标志物是疾病最关键的指标 进展。此外，啮齿动物模型的特征提出了几个 HE/HA的研究中的弱点。由于我们所知的差距，没有 可用于实用有效的临床干预策略 预防或反向生物标志物或疾病的症状。最近，我们有 确定了脊椎动物模型，海湾蟾蜍（Opsanus beta），这两者都是 对氨侮辱的极为宽容，并且由于其水生 生活方式，启用一系列实验，在哺乳动物模型中不实用， 即快速“氨水清洗”方案。因此，我们建议测试几个 旨在利用这些新特征的这些假设 解决HE/HA缺乏生物标志物和干预策略的模型。 特别是：（1）检验有可逆V的假设。 He/ha的不可逆转生物标志物，可以很容易地识别出来 在像蟾蜍这样的水生模型中区分； （2）检验假设 相对于哺乳动物，蟾蜍中极端的氨耐受性是由于 特别是更强大的生理学的一个不寻常的方面 大脑中的氨解毒系统，或对 脑线粒体代谢对氨侮辱。作为对此的进一步测试 第二个假设，我们还将探讨蟾蜍有的可能性 较高水平的天然氨保护剂化合物（例如， 与哺乳动物相比，其脑组织中的肉碱，三甲胺等。在 总而言之，这些实验将导致不容易获得的信息 从人类和现有的有关作用机理的哺乳动物模型 氨和细胞的耐受性和恢复能力，因此 更好地了解他/HA的原因和机制 导致治疗策略。

项目成果

Effect of elevated ammonia on tissue nitrogen metabolites in the ureotelic gulf toadfish (Opsanus beta) and the ammoniotelic midshipman (Porichthys notatus).

氨浓度升高对输尿管海湾蟾蜍 (Opsanus beta) 和氨输尿管候补生 (Porichthys notatus) 组织氮代谢的影响。

• DOI: 10.1086/588829
• 发表时间: 2009
• 期刊: Physiological and biochemical zoology : PBZ
• 作者: Veauvy,CM;Walsh,PatrickJ;McDonald,MD
• 通讯作者: McDonald,MD

Greatly elevated urea excretion after air exposure appears to be carrier mediated in the slender lungfish (Protopterus dolloi).

在细长肺鱼（Protopterus dolloi）中，接触空气后尿素排泄量大大增加似乎是载体介导的。

• DOI: 10.1086/432919
• 发表时间: 2005
• 期刊: Physiological and biochemical zoology : PBZ.
• 作者: Wood,ChrisM;Walsh,PatrickJ;Chew,ShitF;Ip,YuenK
• 通讯作者: Ip,YuenK

Ammonia affects brain nitrogen metabolism but not hydration status in the Gulf toadfish (Opsanus beta).

氨会影响海湾蟾蜍（Opsanus beta）的大脑氮代谢，但不会影响水合状态。

• DOI: 10.1016/j.aquatox.2005.05.003
• 发表时间: 2005
• 期刊: Aquatic toxicology (Amsterdam, Netherlands)
• 作者: Veauvy,ClemenceM;McDonald,MDanielle;VanAudekerke,Johan;Vanhoutte,Greet;VanCamp,Nadja;VanderLinden,Annemie;Walsh,PatrickJ
• 通讯作者: Walsh,PatrickJ

Metabolic fate of exogenous 15NH4Cl in the gulf toadfish (Opsanus beta).

海湾蟾蜍 (Opsanus beta) 中外源 15NH4Cl 的代谢命运。

• DOI: 10.1016/s1532-0456(03)00196-0
• 发表时间: 2003
• 期刊: Comparative biochemistry and physiology. Toxicology & pharmacology : CBP
• 作者: Rodicio,LenoreP;Sternberg,LeoneldaSilveiraLobo;Walsh,PatrickJ
• 通讯作者: Walsh,PatrickJ