ANIMAL MODEL OF ARGINASE II DEFICIENCY

这一建议的重点是第二精氨酸酶基因(AII)的研究， 发现于从两栖动物到人类的真核生物中，其目标是 了解其在精氨酸动态平衡中的作用、调节和 最终利用它作为一种替代不足的肝脏的手段 高精氨酸血症和进行性精氨酸血症患者的精氨酸酶活性 神经和智力退化。 AII的cdna和特异性抗体将用于研究AII。 前列腺、肾脏、哺乳期乳腺和巨噬细胞的调节， AII表达特别高的器官和细胞类型。 将作出特别努力，以确定特定的细胞类型和 AII突出的生理环境，如巨噬细胞 青春期激活或前列腺成熟。两国关系 在一氧化氮合酶和精氨酸脱羧酶之间 共享精氨酸作为底物，也将被研究。所有的老鼠 用克隆的方法克隆并鉴定129Sv基因 老鼠。这一知识将被用来创造一个缺乏AII的淘汰赛 动物来定义它的表型，来定义基因的功能 产品，以了解其敲除对精氨酸的影响 动态平衡及其对AI和其他基因表达的影响 精氨酸酶(如果存在)。 最终形成了各种缺陷的AI和AII基因组合 从人工智能和所有部分或全部缺陷动物的杂交中 提供原材料来概念化一系列战略，从 基因激活到基因治疗，用于治疗AI(并最终 所有不足之处。

This proposal focuses on the study of the second arginase gene (AII), found in eucaryotes from amphibians to man, with the goal of understanding its role in arginine homeostasis, its regulation and ultimately in exploiting it as a means of replacing deficient liver arginase (AI) activity in patients with hyperargininemia and progressive neurological and intellectual deterioration. The cDNA and specific antibodies to AII will be used to study AII regulation in prostate kidney, lactating mammary gland and macrophages, organs and cell types in which AII expression is particularly high. Special efforts will be made to define specific cell types and physiological circumstances in which AII is prominent, such a macrophage activation or prostate maturation with puberty. The relationship between AII, nitric oxide synthetase and arginine decarboxylase, enzymes sharing arginine as a substrate, will be studied as well. The mouse AII cDNA clone will be used to clone and characterize the gene in 129Sv mice. This knowledge will be used to create an AII-deficient knockout animal to define its phenotype, to define the functions of the gene product, to understand the impact of its knockout on arginine homeostasis and to define its impact on the expression of AI and other arginases (if they exist). Ultimately various combinations of deficient AI & AII genes developed from crosses of AI and AII partially or wholly deficient animals will provide the raw material to conceptualize a series of strategies, from gene activation to gene therapy, for the treatment of AI (and ultimately AII) deficiencies.