Studying the Physiological Role of Nuak1 in Tau Pathogenesis

 描述(申请人提供)：许多神经退行性疾病，如阿尔茨海默病(AD)和前颞叶变性(FTLD)，都有一个共同的致病机制：tau蛋白的异常积聚，要么是由于影响其清除的突变，要么是由于其他因素阻碍野生型tau的降解。佐格比实验室提出，识别控制tau水平的基因和基因网络将揭示tau驱动的痴呆的潜在治疗切入点。为此，我们在人类细胞和含有表达tau基因的果蝇中进行了正向基因敲除筛选。这一方法揭示了下调一种AMPK相关的激酶NUAK1，降低了人类细胞和果蝇中的tau水平，并抑制了tau表达的果蝇的神经退化。激酶是很重要的研究对象，因为它们是很好的药理靶点，而NUAK1则是一个潜在的药物靶点。我建议的最重要的假设是了解NUAK1参与tau发病的机制，这将有助于更好地理解tau病和相关的神经退行性疾病。在该奖项的指导阶段，我将通过在小鼠身上的遗传相互作用研究以及生化方法来确定NUAK1在tau发病机制中的作用。这些研究将在贝勒医学院胡达·佐格比博士的实验室进行。佐格比博士有对科学做出杰出贡献的历史，也长期致力于指导年轻科学家。作为一名独立的研究人员，我将确定NUAK1和tau之间的生理和功能相互作用，研究这种相互作用如何调节轴突分支，以及NUAK1-tau复合体的解除调控如何触发病理性tau积聚。此外，我将确定Aü在NUAK1激活和随后的tau毒性积累中的潜在作用。这些研究将为研究NUAK1的功能及其与以tau病理性积聚为特征的神经退行性疾病的相关性提供平台。从这些研究中获得的信息可能会导致开发出针对这类神经退行性疾病的有效疗法。

 DESCRIPTION (provided by applicant): Many neurodegenerative disorders, such as Alzheimer disease (AD) and Front temporal lobar degeneration (FTLD), share a common pathogenic mechanism: the abnormal accumulation of tau protein, either due to a mutation that affects its clearance or due to other factors that retard the degradation of wild type tau. The Zoghbi lab has proposed that identifying genes and genes networks that control the level of tau will reveal potential therapeutic entry points for tau-driven dementias. To this end we performed forward genetic knock- down screens in both human cells and Drosophila harboring genes that express tau. This approach revealed that down regulation of Nuak1, an AMPK-related kinase, decreases tau levels in human cells and in fruit-flies, and suppresses neurodegeneration in tau-expressing Drosophila. Kinases are important to study because they are excellent pharmacologic targets, and Nuak1 stands out as a potential drug target. The overarching hypothesis of my proposal is to understand the mechanisms by which Nuak1 contributes to tau pathogenesis, which will lead to a better understanding of tauopathies and related neurodegenerative diseases. During the mentored phase of the award, I will determine the role of Nuak1 in tau pathogenesis through genetic interaction studies in mice as well as biochemical approaches. These studies will be performed in Dr. Huda Zoghbi's laboratory at Baylor College of Medicine. Dr. Zoghbi has a history of outstanding contributions to science as well as a longstanding commitment to the mentorship of young scientists. As an independent investigator, I will determine the physiological and functional interactions between Nuak1 and tau, investigate how this interaction regulates axonal branching, and how the deregulation of Nuak1-tau complex triggers pathological tau accumulation. Furthermore, I will identify the potential role of Aß on Nuak1 activation and the subsequent toxic accumulation of tau. The proposed studies will provide a platform for investigation of Nuak1 function and its relevance to neurodegenerative diseases characterized by the pathological accumulation of tau. Information gained from these studies might lead to the development of effective therapeutics for this subset of neurodegenerative diseases.