Argininosuccinate Lyase is an essential regulator of systemic nitric oxide produc

描述（由申请人提供）：一氧化氮（NO）是多种生理和疾病过程的重要信号分子。虽然NO通量的调节主要集中在三种NO合成酶（NOS）的研究上，但它们各自的遗传缺陷表现出相对温和的表型。这导致了在不同的疾病过程中解剖特定的细胞对NO的贡献的困难。相反，假设的精氨酸底物在指定NO通量的细胞内区室化可用性可以解释“精氨酸悖论”。“在人类中，尿素循环障碍的自然史，特别是由乙酰氨基琥珀酸裂解酶（ASL）缺乏引起的乙酰氨基琥珀酸尿症（阿萨），显示出全身性和慢性特征，可能反映了NO稳态的整体失调。我们建议，ASL实际上是NO稳态的中央调节器，因为它是必不可少的精氨酸的细胞内生产和利用细胞外精氨酸。在初步的数据，我们确定了一个独特的亚细胞和生化隔室，局部细胞精氨酸生产和通道ASL调节系统NO的生产。我们已经创建了Asl缺乏症的条件遗传模型，这将使我们能够研究大脑（神经元与神经胶质细胞）、心血管系统（内皮细胞与平滑肌细胞）和胰腺β细胞中细胞自主损失NO的后果，这对了解NO对神经退行性疾病、心血管疾病和代谢综合征模型的贡献具有广泛的影响。在生化水平上，我们将评估ASL如何控制精氨酸的可用性，以产生NO。我们的研究可能会发现新的和更有效的策略操纵NO在多系统疾病。

DESCRIPTION (provided by applicant): Nitric Oxide (NO) is an essential signaling molecule for diverse physiological and disease processes. While the regulation of NO flux has focused primarily on the study of the three NO synthases (NOS), their respective genetic deficiencies exhibit relatively modest phenotypes. This has led to difficulties in dissecting the specific cellular contributions to NO in different disease processes. In contrast, the hypothesized intracellular compartmentalized availability of arginine substrate in specifying NO flux may explain the "arginine paradox." In humans, the natural history of urea cycle disorders and specifically of argininosuccinic aciduria (ASA) caused by deficiency of argininosuccinic acid lyase (ASL) shows systemic and chronic features that may reflect global dysregulation of NO homeostasis. We propose that ASL is in fact the central regulator of NO homeostasis because it is essential for both the intracellular production of arginine and the utilization of extracellular arginine. In preliminary data, we identify a distinct subcellular and biochemical compartment where local cellular arginine production and channeling by ASL regulates systemic NO production. We have generated a conditional genetic model of Asl deficiency that will allow us to study the consequences of cell autonomous loss of NO in brain (neurons vs. glial cells), the cardiovascular system (endothelial vs. smooth muscle cells), and the pancreatic beta cell with broad implications on understanding the contribution of NO to models of neurodegeneration, cardiovascular disease, and metabolic syndrome. On a biochemical level, we will assess how ASL controls arginine availability for NO production. Our studies may identify novel and more effective strategies for manipulation NO in multi-system disease.