Metabolic Regulation of Neurodegeneration in Tauopathy

Tau 蛋白病神经变性的代谢调节

• 批准号: 9321947
• 负责人: Xu Chen
• 金额: $ 13.33万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321947
• 关键词: 5' -AMP-activated protein kinase; Ablation; Acetylation; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Animals; Area; Autophagocytosis; Behavior; Brain; Brain Diseases; Brain region; Candidate Disease Gene; Cells; Cognitive; Cognitive deficits; Country; Critical Pathways; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Drosophila genus; EP300 gene; Elderly; Enhancers; Eye; Frontotemporal Lobar Degenerations; Functional disorder; Funding; Genes; Genetic; Genetic Models; Genetic Screening; Glucose; Goals; Impaired cognition; In Vitro; Insulin Resistance; Knock-out; Knowledge; Laboratories; Laboratory Research; Link; Longevity; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Microtubule-Associated Proteins; Modeling; Molecular; Mus; Mutagenesis; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Obesity; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pharmacology; Phase; Phenotype; Phosphorylation; Population; Protein Kinase; Regulation; Research; Risk; Role; Signal Pathway; Starvation; System; Tauopathies; Testing; Training; United States National Institutes of Health; age related; base; fly; in vivo; interdisciplinary approach; metabolic abnormality assessment; molecular targeted therapies; mouse model; neuropathology; neuroprotection; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; nutrient deprivation; overexpression; p300/CBP-Associated Factor; protective effect; sensor; skills; tau Proteins; tau aggregation; tau mutation; tool

PROJECT SUMMARY/ABSTRACT Neurodegenerative diseases and metabolic disorders are common in the elderly population. Tauopathies, such as Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau inclusions, are the most prevalent neurodegenerative diseases in the US and worldwide. There is no cure, and the few available treatments have limited efficacy. Therefore, novel molecular targets and new therapies are urgently needed. The hallmark of tauopathy is the accumulation of tau, a microtubule-associated protein, in the brain, leading to progressive cognitive decline and neurodegeneration. Tau accumulation in brain regions coincides with areas of glucose hypometabolism, implicating metabolic dysregulation in those areas, and metabolic disorders such as type2 diabetes increase the risk of developing AD. However, it is unclear which signaling pathways are critically involved in metabolic dysregulation in tauopathy brains, whether they contribute to neurodegeneration, and what the underlying molecular mechanisms are. In preliminary studies, I discovered that AMPK—a key energy sensor and regulator in cells—is dysregulated in tauopathy animals, which might contribute to the accumulation of pathogenic tau. This study aims to use multidisciplinary approaches to elucidate how metabolic dysregulation modulates tau-mediated neurodegeneration, focusing on defining the mechanistic role of AMPK in tauopathy models. Specifically, I will determine whether AMPK regulates tau-mediated neurodegeneration in tauopathy mouse models (Aim 1) and dissect the mechanism underlying the neuroprotective effect of AMPK (Aim 2). Based on my preliminary research, I will test the hypothesis that AMPK protects against tau-mediated neurodegeneration by a) inhibiting p300-induced tau acetylation and b) enhancing autophagy, in mouse and fly models. I will assess how metabolic changes effect AMPK- p300/autophagy pathways and tau pathology in tauopathy brain (Aim 3). Finally, I will perform a genetic screen in Drosophila to identify novel genes and pathways that regulate metabolic deficits in tauopathy animals, and investigate the roles of these regulators in tau-mediated neurodegeneration (Aim 4). In the mentored phase, I will continue to use fly genetics and in vitro and in vivo tauopathy models, and acquire additional skills in mouse genetic models and metabolic characterization. This training I receive will enable me to complete the proposed studies and launch an independent research laboratory within 2 years. Completion of my proposed studies will provide a proof of concept for targeting AMPK pathway for tauopathy treatment, and enable me to establish a working system beginning from identification of new regulators of tau-dependent metabolic deficits and neurodegeneration, to mechanistic studies using multi-disciplinary approaches, to provide basis formulating new therapeutic strategies for treating neurodegenerative diseases. The K99/R00 mechanism will provide the support necessary to advance my goal of successfully establishing an NIH R01-funded, independent laboratory to study metabolic regulation of neurodegeneration.

项目总结/摘要 神经退行性疾病和代谢紊乱在老年人群中很常见。Tauopathies，such 如阿尔茨海默病（AD）和额颞叶变性伴tau蛋白夹杂物，是最常见的 神经退行性疾病在美国和世界各地。没有治愈的方法，而且为数不多的可用治疗方法 有限的功效。因此，迫切需要新的分子靶点和新的治疗方法。的标志 tau蛋白病是tau蛋白（一种微管相关蛋白）在脑中的积累，导致进行性脑损伤。 认知能力下降和神经退化Tau在大脑区域的积累与葡萄糖区域一致 代谢减退，涉及这些区域的代谢失调，以及代谢紊乱，如2型 糖尿病会增加患AD的风险。然而，目前还不清楚哪些信号通路是关键的， 参与tau蛋白病大脑中的代谢失调，无论它们是否有助于神经变性， 潜在的分子机制是什么。在初步研究中，我发现AMPK-一种关键的能量 细胞中的传感器和调节器-在tau蛋白病动物中失调，这可能有助于 致病性tau的积累。本研究旨在使用多学科的方法来阐明如何 代谢失调调节tau蛋白介导的神经退行性变，重点是定义其机制作用 AMPK在tau蛋白病模型中的表达。具体来说，我将确定AMPK是否调节tau介导的 研究tau蛋白病小鼠模型中的神经变性（目的1），并剖析tau蛋白病小鼠模型中神经变性的机制。 AMPK的神经保护作用（目的2）。根据我的初步研究，我将测试的假设， AMPK通过a）抑制p300诱导的tau乙酰化和B） 在小鼠和苍蝇模型中增强自噬。我将评估代谢变化如何影响AMPK- p300/自噬途径和tau病变脑中的tau病理学（Aim 3）。最后，我将进行基因筛查 在果蝇中鉴定调节tau蛋白病动物代谢缺陷的新基因和途径， 研究这些调节因子在tau介导的神经变性中的作用（Aim 4）。在学习阶段，我 将继续使用苍蝇遗传学和体外和体内tau蛋白病模型，并获得额外的技能， 小鼠遗传模型和代谢表征。我接受的培训将使我能够完成 建议研究，并在两年内启动一个独立的研究实验室。完成我提出的 研究将为靶向AMPK通路治疗tau蛋白病提供概念证明，并使我能够 从鉴定tau依赖性代谢缺陷的新调节剂开始建立工作系统 和神经退行性变，使用多学科方法进行机制研究， 为治疗神经退行性疾病制定新的治疗策略。K99/R 00机构将 提供必要的支持，以推进我成功建立一个NIH R 01资助的目标， 独立实验室研究神经变性的代谢调节。