Argininosuccinate Lyase is an essential regulator of systemic nitric oxide produc

说明书(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。虽然对NO通量的调节主要集中在对三种一氧化氮合酶(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。这导致了在分析不同疾病过程中细胞对NO的具体贡献方面的困难。相反，假设细胞内精氨酸底物在规定无通量时的可分隔性，可能解释了“精氨酸悖论”。在人类中，尿素循环紊乱的自然病史，特别是精氨酸琥珀酸裂解酶(ASL)缺乏引起的精氨酸尿症(ASA)，显示出系统性和慢性特征，可能反映了全球NO稳态的失调。我们认为ASL实际上是NO稳态的中枢调节器，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隔室，在那里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ASL缺乏的条件遗传模型，这将使我们能够研究细胞自主丢失NO在脑(神经细胞与神经胶质细胞)、心血管系统(内皮细胞与平滑肌细胞)和胰腺β细胞中的后果，这对于理解NO在神经退行性变、心血管疾病和代谢综合征模型中的作用具有广泛的意义。在生化水平上，我们将评估ASL如何控制精氨酸在不生产的情况下可用。我们的研究可能会发现在多系统疾病中操纵NO的新的、更有效的策略。 与公共卫生相关：一氧化氮(NO)是导致几乎所有人类疾病的重要分子。我们建议研究一种新的方法来研究一氧化氮是如何在体内产生的。一种名为精氨酸琥珀酸裂解酶(ASL)的化学物质被用来产生精氨酸，而精氨酸是产生NO所必需的。我们将确定抑制ASL是否可能是控制影响大脑、心脏和胰腺疾病的NO产生的最有效方法。

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.