HUMAN ARGINASE AND ARGINASE DEFICIENCY

本研究的重点是研究和开发人类精氨酸酶I （AI）缺乏和高精氨酸血症的小鼠敲除模型，这是一种导致神经和智力退化并导致智力迟钝的疾病。该模型将用于阐明人类两种精氨酸酶基因（AI和AII）的功能、调控和进化，以及阐明AI缺乏症的病理和病理生理。长期目标是设计策略来替代精氨酸酶在这些患者或以其他方式减轻高精氨酸血症的影响。这些疗法包括基因疗法和诱导AII或“自体酶替代疗法”。本研究将对ai缺乏型高精氨酸血症小鼠进行高氨血症保护后的生物化学、分子生物学和病理学研究。使用的方法包括：血浆和组织氨基酸测量；酶测定;免疫沉淀反应;免疫组织化学;原位杂交；动物行为测试；组织培养。研究将测试高精氨酸血症、过量一氧化氮（NO）产生和神经递质谷氨酸和/或γ氨基丁酸（GABA）合成增加的两种不同的神经损伤假设。AI和AII敲除动物将被用来探索这两种精氨酸酶在炎症细胞、前列腺功能和肾脏生化中的作用。一种或另一种精氨酸酶转基因在不同组织中的表达将在这些研究中发挥重要作用。本项目利用独特的模型，在合适的时间、理想的环境和理想的合作者，研究导致智力迟钝的代谢性疾病的影响，并通过基因操纵治疗。这些研究的结果应该为这类疾病提供更多的相关信息。

This proposal focuses on the study and exploitation of the mouse knockout model for human arginase I (AI) deficiency and hyperargininemia, a condition which causes neurological and intellectual deterioration and which results in mental retardation. The model will be used to elucidate the function, regulation and evolution of the two arginase genes in man (AI and AII) and to elucidate the pathology and pathophysiology of AI deficiency. The long term goal is to devise strategies to replace arginase in these patients or otherwise mitigate the impact of the hyperargininemia. These will include gene therapy and induction of AII or "autoenzyme replacement therapy". The biochemistry, molecular biology, pathology of the AI-deficient hyperarginemic mouse after protecting it from hyperammonemia will be studied. Approaches used include: plasma and tissue amino acid measurement; enzyme assay; immunoprecipitation; immunohistochemistry; in situ hybridization; animal behavioral testing; and tissue culture. Studies will test two distinct hypotheses for the neurological damage in hyperargininemia, excess nitric oxide (NO) production and increased synthesis of the neurotransmitters, glutamate and/or gamma aminobutyric acid (GABA). The AI and AII knockout animals will e used to explore the role of the two arginases in inflammatory cells, prostate function and kidney biochemistry. Expression of one or the other arginase transgenes in different tissues will play a prominent role in these studies. This project exploits unique models, at a propitious time, in an ideal environment and with ideal collaborators, to study the effects of a metabolic disease that causes mental retardation, and its treatment by gene manipulation. Results from these studies should provide relevant to a larger number of disorders of this type.