Studying the Physiological Role of Nuak1 in Tau Pathogenesis

 描述（由申请人提供）：许多神经退行性疾病，如阿尔茨海默病（AD）和前颞叶变性（FTLD），具有共同的致病机制：tau蛋白的异常积累，这是由于影响其清除的突变或由于阻碍野生型tau降解的其他因素。Zoghbi实验室提出，识别控制tau水平的基因和基因网络将揭示tau驱动痴呆症的潜在治疗切入点。为此，我们在人类细胞和果蝇中进行了正向基因敲除筛选，这些细胞含有表达tau的基因。这种方法揭示了Nuak 1（一种AMPK相关激酶）的下调降低了人类细胞和果蝇中的tau水平，并抑制了表达tau的果蝇中的神经变性。激酶的研究很重要，因为它们是极好的药理学靶点，而Nuak 1是一个潜在的药物靶点。我的建议的首要假设是了解Nuak 1有助于tau发病机制的机制，这将导致更好地了解tau蛋白病和相关的神经退行性疾病。在该奖项的指导阶段，我将通过小鼠遗传相互作用研究以及生物化学方法确定Nuak 1在tau发病机制中的作用。这些研究将在贝勒医学院的Huda Zoghbi博士实验室进行。Zoghbi博士对科学有着杰出贡献的历史，并长期致力于指导年轻科学家。作为一名独立的研究者，我将确定Nuak 1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Nuak 1-tau复合物的失调如何触发病理性tau积累。此外，我还将确定April对Nuak 1激活和随后的tau毒性积累的潜在作用。拟议的研究将为研究Nuak 1功能及其与以tau病理性积累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有效的治疗这一子集的神经退行性疾病。

 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.