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Emerging Roles of Higher-order Polyamines During Tauopathies

高阶多胺在 Tau蛋白病中的新作用

基本信息

批准号：
10224543
负责人：
Daniel Carl Lee
金额：
$ 47.1万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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/10224543
关键词：
Acetylation Affect Age Alzheimer&apos s Disease American Anabolism Animal Model Arginine Autophagocytosis Axon Back Behavioral Caring Catabolism Cell Culture Techniques Cells Cessation of life Cognition DL-alpha-Difluoromethylornithine Data Dependovirus Deposition Diagnosis Diet Dietary Administration 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 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 tau-1 therapeutic target transcription factor

项目摘要

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.

包括阿尔茨海默病(AD)在内的各种疾病总共影响了近600万美国人，造成超过 2000亿美元的医疗保健。他们摧毁了家庭，使受害者失去了记忆和尊严，最后，他们的身份。目前还没有用于治疗紧张性疾病的疾病修饰剂，而AD和目前尚不清楚患者是否能自行康复；被诊断为肌萎缩侧索硬化症等于被判死刑。建议的战略以减少tau负担包括增加清除量，减少磷酸化或硝化，减少聚集，以及消炎等。精氨酸代谢处于一个关键的分支点，是一氧化氮合酶生成一氧化氮的前体，或从精氨酸酶(Arg1)。我们的数据表明，在紧张症小鼠模型中Arg1的过度表达减少了 Tau表型的各个方面：磷酸化tau沉积，Gallyas染色，海马区萎缩，高分子体重tau多聚体、tau硝化、炎症细胞因子标记物、自噬抑制物和蛋白质激活酶的激活。这些效应中的许多也可以在细胞培养中得到证明。我们还表明，更高的- 有序多胺直接阻断tau聚集，促进微管聚集浓度，但乙酰多胺不能模拟这种影响。这种操作的几个明显影响可以介导Arg1的过度表达和多胺代谢的这些显着好处。这样做的目的是应用是为了更好地理解多胺如何有助于减少tau表型的好处，并确定治疗肥胖症和可能的阿尔茨海默病的其他潜在靶点。利用基因疗法，小鼠牵牛术模型和击倒模型我们将测试四个目标。1)确定增加的多胺是否减少Tau病理。2)确定减少的多胺是否促进Tau的病理改变。3)测试是否多胺的药理营养调节调节Tau的病理和4)检测是否缺失 SSAT可降低Tau病理改变。这些目标的成功将增加我们对多胺代谢对tau表型的调节作用。我们的目标是确定更多的治疗靶点这可以由药物调节，以阻止或减缓tau沉积的进展患有神经退行性疾病的人类。