Argininosuccinate Lyase is an essential regulator of systemic nitric oxide produc

描述（申请人提供）：一氧化氮（NO）是多种生理和疾病过程中必不可少的信号分子。虽然NO通量的调控主要集中在对三种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。这导致了在不同疾病过程中解剖一氧化氮的特定细胞贡献的困难。相反，假设细胞内精氨酸底物在指定NO通量时的分区可用性可以解释“精氨酸悖论”。在人类中，由精氨酸琥珀酸裂解酶（ASL）缺乏引起的尿素循环障碍，特别是精氨酸琥珀酸尿症（ASA）的自然历史显示出系统性和慢性特征，可能反映了NO稳态的全局失调。我们认为，ASL实际上是一氧化氮稳态的中心调节器，因为它对细胞内精氨酸的产生和细胞外精氨酸的利用都是必不可少的。在初步数据中，我们确定了一个独特的亚细胞和生化室，其中局部细胞精氨酸的产生和ASL的通道调节全身NO的产生。我们已经建立了一个Asl缺乏的条件遗传模型，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NO细胞自主损失的后果，这对理解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意义。在生化水平上，我们将评估ASL如何控制NO生产的精氨酸可用性。我们的研究可能会发现新的和更有效的策略来操纵一氧化氮在多系统疾病。

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. PUBLIC HEALTH RELEVANCE: Nitric oxide (NO) is an important molecule in the cause of almost all human diseases. We propose to study a new way on how NO is produced in the body. A chemical called argininosuccinate lyase (ASL) is used to produce arginine which is required for NO production. We will determine whether inhibiting ASL may be the most effective way for controlling NO production in diseases affecting the brain, heart, and pancreas.