Extreme Ammonia Tolerance Mechanisms: A Model Vertebrate

描述（由申请方提供）：肝性脑病（HE）及其结果 升高的血液和组织氨浓度（即，高氨血症，HA）， 具有深刻的中枢神经系统（CNS）影响，并可具有环境 可使.特别是，由于暴露于有毒物质（如碳）而导致的肝损伤 四氯化碳、甲苯、滴滴涕、七氯等，以及慢性酒精中毒 和直接暴露于环境氨，可以引起HE/HA的症状。 然而，有这样一个广泛的各种中枢神经系统的影响产生的疾病 在人类和啮齿动物实验模型中， 哪些疾病生物标志物是疾病最重要的指标 进展此外，啮齿动物模型的特征呈现出几个方面。 HE/HA研究中的薄弱环节。由于我们知识上的差距， 有切实有效的临床干预策略， 预防或逆转疾病的生物标志物或症状。最近我们 确定了一个脊椎动物模型，海湾蟾鱼（Opsanus beta），这是两者兼而有之 非常耐氨的侮辱，并凭借其水生 生活方式，使一系列实验在哺乳动物模型中不切实际， 即快速“氨洗出”方案。因此，我们建议测试几个 假设旨在利用这些和其他特点，这一新的 该模型旨在解决HE/HA缺乏生物标志物和干预策略的问题。 具体而言，我们将：（1）检验存在可逆vs. HE/HA的不可逆生物标志物，并且这些生物标志物可以容易地识别， 区别于水生模型，如蟾鱼;（2）测试假设 相对于哺乳动物而言，蟾鱼对氨的耐受性极强， 特别是，它的生理学的一个不寻常的方面，要么是一个更强大的 氨解毒系统在大脑中，或一个固有的不敏感性， 脑线粒体代谢到氨损伤。作为进一步的测试 第二个假设，我们也将探讨蟾鱼有可能 更高水平的天然存在的氨保护剂化合物（例如， 肉毒碱、氧化三甲胺等）比哺乳动物的脑组织更丰富。在 总而言之，这些实验将导致不易获得信息 从人类和现有的哺乳动物模型有关的作用机制 氨和细胞的耐受性和恢复能力，因此， 更好地了解HE/HA的原因和机制， 导致治疗策略。

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.