Metabolic Regulation of Neurodegeneration in Tauopathy

Tau 蛋白病神经变性的代谢调节

基本信息

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
项目类别：
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&apos -AMP-activated protein kinase Ablation Acetylation Affect Alzheimer&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要/摘要神经退行性疾病和代谢紊乱在老年人群中很常见，例如 Tau蛋白病。阿尔茨海默病 (AD) 和额颞叶变性伴 tau 蛋白包涵体是最常见的在美国和世界范围内，神经退行性疾病无法治愈，而且可用的治疗方法也很少。因此，迫切需要新的分子靶点和新疗法。 tau蛋白病是tau蛋白（一种微管相关蛋白）在大脑中的积累，导致进行性进展认知能力下降和神经退行性变与大脑区域中 Tau 蛋白的积累相一致。代谢低下，意味着这些区域的代谢失调，以及代谢紊乱，例如 2 型糖尿病会增加患 AD 的风险，但目前尚不清楚哪些信号通路至关重要。参与 tau 蛋白病大脑代谢失调，是否会导致神经退行性变，以及在初步研究中，我发现了 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，这可能导致本研究旨在利用多学科方法来阐明致病性 tau 蛋白的积累。代谢失调调节 tau 介导的神经变性，重点是确定其机制作用具体来说，我将确定 AMPK 是否调节 tau 介导的。 tau蛋白病小鼠模型中的神经退行性变（目标1）并剖析其背后的机制 AMPK 的神经保护作用（目标 2）。根据我的初步研究，我将检验以下假设： AMPK 通过 a) 抑制 p300 诱导的 tau 乙酰化和 b) 防止 tau 介导的神经变性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 蛋白病大脑中的 tau 病理学（目标 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，以及研究这些调节因子在 tau 介导的神经变性中的作用（目标 4）。将继续使用果蝇遗传学以及体外和体内 tau 蛋白病模型，并获得以下方面的额外技能我将接受的小鼠遗传模型和代谢表征培训将使我能够完成提议的研究并在两年内启动一个独立的研究实验室。研究将为针对 tau 蛋白病治疗的 AMPK 通路提供概念证明，并使我能够从识别 tau 依赖性代谢缺陷的新调节因子开始建立工作系统和神经退行性疾病，利用多学科方法进行机制研究，提供基础制定治疗神经退行性疾病的新治疗策略。提供必要的支持，以推进我成功建立 NIH R01 资助的目标，研究神经变性代谢调节的独立实验室。