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：
10251367
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251367
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 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，造成的损失超过价值 2000 亿美元的医疗服务给家庭带来了毁灭性的打击，让受害者失去了记忆、尊严，并且，最后，目前还没有用于治疗 tau 病、AD 和 AD 的疾病调节药物。自发恢复尚不清楚；诊断出 tau 蛋白病就等于宣判了死刑。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。精氨酸代谢正处于关键的分支点。作为一氧化氮合酶产生一氧化氮或从多胺产生的前体我们的数据表明，在 tau 蛋白病小鼠模型中，Arg1 过度表达。 tau 表型方面；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许多这些效应也可以在细胞培养中得到证明。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。可以介导 Arg1 过度表达和多胺代谢的这些显着益处。应用是为了更好地了解多胺如何有助于减少 tau 表型，并确定利用基因疗法治疗 tau 病和 AD 的其他潜在靶点。对于 tau 蛋白病模型和基因敲除模型，我们将测试四个目标 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增强 Tau 病理学。多胺的药理营养调节调节 Tau 病理学，4) 测试是否删除 SSAT 减少 Tau 病理学的成功将增加我们对 Tau 蛋白作用的认识。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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis.

DOI：
10.3389/fimmu.2020.582998
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Ma C;Hunt JB;Selenica MB;Sanneh A;Sandusky-Beltran LA;Watler M;Daas R;Kovalenko A;Liang H;Placides D;Cao C;Lin X;Orr MB;Zhang B;Gensel JC;Feola DJ;Gordon MN;Morgan D;Bickford PC;Lee DC
通讯作者：
Lee DC

Myeloid Arginase 1 Insufficiency Exacerbates Amyloid-β Associated Neurodegenerative Pathways and Glial Signatures in a Mouse Model of Alzheimer's Disease: A Targeted Transcriptome Analysis.

DOI：
10.3389/fimmu.2021.628156
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Ma C;Hunt JB;Kovalenko A;Liang H;Selenica MB;Orr MB;Zhang B;Gensel JC;Feola DJ;Gordon MN;Morgan D;Bickford PC;Lee DC
通讯作者：
Lee DC