Emerging Roles of Higher-order Polyamines During Tauopathies

高阶多胺在 Tau蛋白病中的新作用

• 批准号: 9220085
• 负责人: Daniel Carl Lee
• 金额: $ 54.02万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220085
• 关键词: Acetylation; Affect; Age; Alzheimer' s Disease; American; Anabolism; Animal Model; Arginine; Autophagocytosis; Back; Behavioral; Caring; Catabolism; Cell Culture Techniques; Cells; Cessation of life; Cognition; DL-alpha-Difluoromethylornithine; Data; Dependovirus; Deposition; Diagnosis; Diet; Disease; Drug Targeting; Enzymes; Family; Functional disorder; Generations; Goals; Human; Inflammation; Knock-out; Knockout Mice; Knowledge; Learning; Length; Measures; Mediating; Medical; Memory; Metabolism; Microtubules; Modeling; Molecular Weight; Mus; Neurodegenerative Disorders; Neurons; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nutritional; Ornithine; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Polyamine Catabolism; Polyamines; Production; Protein Kinase; Proteins; Recovery; Regulation; Reporting; Role; Spermidine; Spermidine Synthase; Spermine; Spermine Synthase; Staining method; Stains; Supplementation; System; Tauopathies; Testing; Therapeutic; Transferase; Transgenic Mice; age related; arginase; behavioral outcome; biological adaptation to stress; chronic traumatic encephalopathy; cost; cytokine; gene therapy; hippocampal atrophy; inflammatory marker; inhibitor/antagonist; mouse model; nitration; novel; ornithine decarboxylase antizyme; overexpression; response; success; tau Proteins; tau aggregation; therapeutic target; transcription factor

Collectively tauopathies including Alzheimer’s disease (AD) impact close to 6 million Americans and cost over $200 billion in medical care. They devastate families and cause victims to lose their memory, their dignity and, finally, their identity. Currently no disease modify agents exist for treating tauopathies, and AD and spontaneous recovery is unknown; a diagnosis of tauopathy is a death sentence. Strategies proposed to reduce tau burden include increasing clearance, decreasing phosphorylation or nitration, reducing aggregation, and diminishing inflammation, among others. Arginine metabolism is poised at a critical branch-point and serves as a precursor for nitric oxide generation from nitric oxide synthases or polyamine production from arginase (Arg1). Our data indicates that Arg1 overexpression in a mouse model of tauopathy reduces multiple aspects of the tau phenotype; phospho-tau deposition, Gallyas staining, hippocampal atrophy, high molecular weight tau multimers, tau nitration, cytokine markers of inflammation, inhibitors of autophagy, and protein kinase activation. Many of these effects can also be demonstrated in cell culture. We also show that higher- order polyamines directly block tau aggregation and promote microtubule assembly in solution at physiological concentrations, but acetylated polyamines fail to mimic this affect. Several distinct effects of this manipulation could mediate these remarkable benefits of Arg1 over expression and polyamine metabolism. The goal of this application is to better understand how polyamines contribute to the benefits of reducing the tau phenotype, and identify other potential targets for treating tauopathies and possibly AD. Utilizing gene therapy, mouse models of tauopathy, and knockout models we will test four aims. 1) Determine if Increased Polyamines Diminish Tau Pathology. 2) Determine if Reduced Polyamines Enhance Tau Pathology. 3) Test if Pharmacological Nutritional Modulation of Polyamines Regulates Tau Pathology and 4) Test if the Deletion of SSAT Reduces Tau Pathology. Success in these aims will increase our knowledge regarding the role of polyamines metabolism in regulating the tau phenotype. Our goal is to identify additional therapeutic targets that could be regulated by pharmacological agents to arrest or slow the progression of the tau deposition in humans with neurodegenerative disease.

包括阿尔茨海默氏病 (AD) 在内的 tau蛋白病总共影响了近 600 万美国人，造成的损失超过 2000亿美元的医疗保健。它们摧毁了家庭，导致受害者失去记忆、尊严， 最后，他们的身份。目前尚无用于治疗 tau 病、AD 和 自发恢复未知；诊断出 tau 蛋白病就等于宣判了死刑。提议的策略 减少 tau 负担包括增加清除率、减少磷酸化或硝化、减少聚集、 以及减少炎症等。精氨酸代谢处于一个关键的分支点 作为一氧化氮合酶产生一氧化氮或从多胺产生的前体 精氨酸酶（Arg1）。我们的数据表明，在 tau 蛋白病小鼠模型中，Arg1 过度表达可减少多个 tau 表型的各个方面；磷酸tau沉积、Gallyas染色、海马萎缩、高分子 重量 tau 多聚体、tau 硝化、炎症细胞因子标记物、自噬抑制剂和蛋白质 激酶激活。其中许多效应也可以在细胞培养中得到证明。我们还表明，更高 订购多胺直接阻断 tau 聚集并促进生理溶液中的微管组装 浓度，但乙酰化多胺无法模拟这种影响。这种操纵的几个不同的影响 可以介导 Arg1 过度表达和多胺代谢的这些显着益处。此举的目标 应用是为了更好地了解多胺如何有助于减少 tau 表型， 并确定治疗 tau 病和 AD 的其他潜在靶点。利用基因疗法，小鼠 我们将测试 tau 蛋白病模型和基因敲除模型的四个目标。 1) 确定多胺是否增加 减少 Tau 病理学。 2) 确定减少的多胺是否会增强 Tau 病理学。 3）测试是否 多胺的药理学营养调节调节 Tau 病理学，4) 测试是否删除 SSAT 减少 Tau 病理。这些目标的成功将增加我们对以下角色的认识： 多胺代谢调节 tau 表型。我们的目标是确定其他治疗靶点 可以通过药物调节来阻止或减缓 tau 沉积的进展 患有神经退行性疾病的人。