Metabolic Regulation of Neurodegeneration in Tauopathy

项目摘要/摘要 神经退行性疾病和代谢紊乱在老年人群中很常见。焦虑症，诸如此类 由于阿尔茨海默病(AD)和额颞叶变性伴tau包涵体是最常见的 美国和世界各地的神经退行性疾病。没有治愈的方法，而为数不多的可用的治疗方法已经 疗效有限。因此，迫切需要新的分子靶点和新的治疗方法。的标志 Tau病是一种微管相关蛋白tau在大脑中的积聚，导致进行性的 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 代谢不足，意味着这些区域的代谢失调，以及代谢紊乱，如2型 糖尿病会增加患阿尔茨海默病的风险。然而，目前还不清楚哪些信号通路是至关重要的 是否会导致神经退行性变，以及是否会导致神经变性 潜在的分子机制是什么。在初步研究中，我发现AMPK-一种关键能量 细胞中的传感器和调节器-在倒立动物中调节失调，这可能是导致 病原性tau的积聚。这项研究旨在用多学科的方法来阐明 代谢失调调节tau介导的神经退行性变，重点是确定机制作用 AMPK在肌萎缩侧索硬化症模型中的表达。具体地说，我将确定AMPK是否调节tau介导的 大鼠神经退行性变的实验研究(目标1)，并对其发病机制进行剖析。 AMPK的神经保护作用(目标2)。基于我的初步研究，我将检验这一假设 AMPK通过a)抑制p300诱导的tau乙酰化和b)保护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- Tau病脑内P300/自噬通路和tau病理(目标3)。最后，我将进行基因筛查 在果蝇中识别调节共济失调动物代谢缺陷的新基因和新途径，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)。在指导阶段，我 将继续使用苍蝇遗传学和体外和体内的变态反应模型，并在 小鼠遗传模型和代谢特性。我接受的这次培训将使我能够完成 建议进行研究，并在两年内推出独立研究实验室。完成我的建议 研究将为以AMPK通路为靶点治疗肌萎缩侧索硬化症提供一个概念证明，并使我能够 从确定tau依赖性代谢缺陷的新调节器开始，建立工作系统 和神经退行性变，为运用多学科方法进行机械性研究提供依据 为治疗神经退行性疾病制定新的治疗策略。K99/R00机制将 提供必要的支持，以推进我成功建立NIH R01资助的目标， 研究神经退行性变代谢调节的独立实验室。

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.