Arginase and Regulation of Nitric Oxide Synthase in ALS

ALS 中精氨酸酶和一氧化氮合酶的调节

• 批准号: 7313450
• 负责人: Rajiv R Ratan
• 金额: $ 16.14万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313450
• 关键词: amyotrophic lateral sclerosis; apoptosis; arginase; arginine; cell type; cytoprotection; enzyme activity; enzyme induction /repression; genetically modified animals; isozymes; laboratory mouse; neural degeneration; neuroprotectants; neurotoxins; nitric oxide; nitric oxide synthase; oxidative stress; protein localization; superoxide dismutase

DESCRIPTION (Adapted from applicant's abstract): Amyotrophic lateral sclerosis is a prevalent neurological disorder characterized by inexorable muscle weakness leading to death. The principal pathological finding in amyotrophic lateral sclerosis is loss of nerve cells in the anterior horns of the spinal cord, the motor nuclei of the brainstem, and the upper motor neurons of the cerebral cortex. Investigations aimed at preventing or limiting progression of amyotrophic lateral sclerosis have thus focused on the mechanisms by which neurons degenerate. A transgenic mouse model has been developed that possesses many of the pathological and clinical features of human familial and sporadic amyotrophic lateral sclerosis. As nitric oxide (NO) has been shown to mediate neuronal loss in other neurodegenerative conditions, several groups have investigated the role that NO may play in disease progression | in the transgenic model. The results have been conflicting likely because currently available inhibitors of nitric oxide synthase do not permit optimal control of NO generation within particular cell types and subcellular compartments. A novel potential strategy for regulating nitric oxide synthesis involves the enzyme arginase that can | regulate availability of arginine in the cytoplasm or mitochondria. In preliminary studies, we have shown that: 1) extracellular arginase blocks neuronal apoptosis and 2) arginase immunoreactivity is, upregulated in the spinal cord of ALS transgenic mice as well as humans with the sporadic and familial forms of amyotrophic lateral sclerosis. These preliminary results lead to the overall hypothesis to be tested in this proposal: about Interventions aimed at promoting arginase activities in microglia, astrocytes and/or motor neurons will limit availability of cell arginine for toxic NO generation and thereby diminish cell death and disease progression in amyotrophic lateral sclerosis but permit NO to, mediate its survival promoting effects in each of these cell types. We propose to test this hypothesis by: 1) determining the cell types and subcellular compartments where arginase is expressed in the normal central nervous system of humans and mice, and how the localization and levels of these isoforms change in amyotrophic lateral sclerosis as well as in a transgenic mouse! Model of amyotrophic lateral sclerosis and how this compares to the localization of NOS (all forms) in these tissues; and 2) determining whether increased arginase activity in microglia, astrocytes or neurons from control mice or mice over expressing SOD1 mutant (G93A) will abrogate NO mediated toxicity of motor neurons induced by growth factor deprivation, excitotoxins or LPS/IFN-gamma treatment. These studies promise to enhance our understanding of how arginine about metabolism, including the synthesis of NO, is regulated in the normal and abnormal nervous system.

描述（改编自申请人的摘要）：肌萎缩侧索硬化症是一种普遍的神经系统疾病，其特征是肌肉不可抗拒 虚弱导致死亡。肌萎缩侧索硬化症的主要病理学发现 侧索硬化症是脊柱前角神经细胞的损失 脊髓、脑干运动核和上运动神经元 大脑皮层。旨在预防或限制病情进展的研究 因此，肌萎缩侧索硬化症的发病机制已成为人们关注的焦点。 神经元退化。已经开发出一种转基因小鼠模型，该模型具有 人类家族性和散发性的许多病理和临床特征 肌萎缩侧索硬化症。由于一氧化氮 (NO) 已被证明可以介导 其他神经退行性疾病中的神经元损失，一些研究小组发现 研究了一氧化氮在疾病进展中可能发挥的作用在 转基因模型。结果可能是相互矛盾的，因为目前 现有的一氧化氮合酶抑制剂不允许最佳控制 特定细胞类型和亚细胞区室中产生 NO。一个 调节一氧化氮合成的新的潜在策略涉及 精氨酸酶可以|调节细胞质中精氨酸的可用性 或线粒体。在初步研究中，我们已经表明：1）细胞外 精氨酸酶阻断神经元凋亡，2) 精氨酸酶免疫反应性是， ALS 转基因小鼠以及患有 ALS 的人类的脊髓中表达上调 散发性和家族性形式的肌萎缩侧索硬化症。这些 初步结果导致了本次测试的总体假设 提案：关于旨在促进精氨酸酶活动的干预措施 小胶质细胞、星形胶质细胞和/或运动神经元将限制细胞的可用性 精氨酸产生有毒的一氧化氮，从而减少细胞死亡和疾病 肌萎缩侧索硬化症的进展，但允许 NO 介导其 对这些细胞类型中的每一种都有促进生存的作用。我们建议对此进行测试 假设通过：1）确定细胞类型和亚细胞区室，其中 精氨酸酶在人类和小鼠的正常中枢神经系统中表达， 以及这些亚型的定位和水平在肌萎缩侧索硬化症中如何变化 侧索硬化症以及转基因小鼠！肌萎缩模型 侧索硬化症及其与 NOS 定位（所有形式）的比较 在这些组织中； 2) 确定精氨酸酶活性是否增加 来自对照小鼠或过度表达 SOD1 的小鼠的小胶质细胞、星形胶质细胞或神经元 突变体（G93A）将消除 NO 介导的运动神经元毒性 生长因子剥夺、兴奋毒素或 LPS/IFN-γ 治疗。这些 研究有望增强我们对精氨酸如何影响新陈代谢的理解， 包括 NO 的合成，在正常和异常神经中受到调节 系统。

项目成果

Novel roles for arginase in cell survival, regeneration, and translation in the central nervous system.

精氨酸酶在中枢神经系统细胞存活、再生和翻译中的新作用。

• 发表时间: 2004-10
• 作者: Lange, Philipp S;Langley, Brett;Lu, Peiyuan;Ratan, Rajiv R
• 通讯作者: Ratan, Rajiv R

Prolyl 4-hydroxylase activity-responsive transcription factors: from hydroxylation to gene expression and neuroprotection.

脯氨酰 4-羟化酶活性响应转录因子：从羟基化到基因表达和神经保护。

• 发表时间: 2008-01-01
• 作者: Siddiq, Ambreena;Aminova, Leila R;Ratan, Rajiv R
• 通讯作者: Ratan, Rajiv R

ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo.

ATF4 是体外和体内神经元中氧化应激诱导的促死亡转录因子。

• 发表时间: 2008-05-12
• 作者: Lange, Philipp S;Chavez, Juan C;Pinto, John T;Coppola, Giovanni;Sun, Chiao;Townes, Tim M;Geschwind, Daniel H;Ratan, Rajiv R
• 通讯作者: Ratan, Rajiv R

Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons.

抗氧化剂调节线粒体 PKA 并增加 CREB ​​与神经元线粒体基因组 D 环 DNA 的结合。

• 发表时间: 2005-09-27
• 影响因子: 11.1
• 作者: Ryu, Hoon;Lee, Junghee;Impey, Soren;Ratan, Rajiv R;Ferrante, Robert J
• 通讯作者: Ferrante, Robert J

Hypoxia inducible factor prolyl 4-hydroxylase enzymes: center stage in the battle against hypoxia, metabolic compromise and oxidative stress.

缺氧诱导因子脯氨酰 4-羟化酶：对抗缺氧、代谢妥协和氧化应激的中心舞台。

• 发表时间: 2007-04
• 影响因子: 4.4
• 作者: Siddiq, Ambreena;Aminova, Leila R;Ratan, Rajiv R
• 通讯作者: Ratan, Rajiv R