CHIP调控的蛋白质质量控制系统参与阿尔茨海默病发病的分子机制及治疗策略研究

阿尔茨海默病（AD）是机体衰老密切相关的、最常见的神经退行性疾病，深入探讨其发病机制及新的治疗靶标是脑器官衰老研究领域的重大挑战。研究显示：CHIP调控的蛋白质质量控制系统与机体衰老及AD密切相关。我们的前期工作表明：携带CHIP突变的患者和CHIP突变及敲除动物模型均有明显认知功能障碍，在动物模型脑组织中发现AD相关蛋白Tau等表达明显升高，海马神经元丢失。基于以上结果我们推测：CHIP功能障碍参与了脑衰老及向AD演变的分子病理过程，上调CHIP表达对AD可能具有潜在治疗作用。本课题拟应用APP、PS1突变疾病特异性iPS及iPS来源神经元细胞模型、AD转基因动物模型，应用慢病毒、AAV感染及knockin过表达等方法上调CHIP蛋白，从分子、细胞、动物模型等多方面探讨CHIP参与AD发病的分子机制及上调CHIP表达对AD的潜在治疗作用，将为建立AD新的应对策略提供思路，具有重要意义。

Alzheimer's disease (AD) is the most common neurodegenerative disease closely related to aging. Thus it is a vital challenge in the field of aging to explore its molecular pathological mechanism and novel therapeutic targets. Studies have shown that CHIP-regulated protein quality control systems are closely related to aging and AD. Our previous work showed that patients with CHIP mutations and CHIP mutation/knockout animal models had significant cognitive dysfunction. Cognitive dysfunction-related proteins, such as Tau, were significantly increased and hippocampal neurons were lost in brain tissue of the animal model. Based on these findings, we put forward a hypothesis that CHIP dysfunction may be involved in the pathological mechanism of brain aging and AD. Besides, upregulation of CHIP may have potential therapeutic effects on AD. In this study, we will investigate the pathogenesis of CHIP dysfunction in AD and the potential therapeutic effect of up-regulating CHIP by APP,PS1 gene mutation-specific iPS, iPS-derived neuron and mice models. Based on the solid previous work in accordance with the scientific hypothesis and advanced experiment methods, this study is expected to provide a theoretical basis for the establishment of new strategies for AD.