The integrated stress response in cognitive disorders

摘要 认知障碍对公众健康构成重大威胁，并代表着巨大的经济和社会影响。 负担尽管这些疾病的发病率很高，但有效的治疗仍然非常有限。因此 开发治疗认知障碍的新疗法是一个重要的目标。在这里，我们将重点放在 整合应激反应（ISR），一种保守的信号网络，通过以下方式恢复蛋白质稳态： 调节蛋白质合成，以及与记忆缺陷相关的主要致病途径。 广泛的认知障碍这种竞争性更新的目标是定义精确的分子， 细胞和电路机制，通过这些机制ISR的激活导致认知功能障碍。在目标1中，我们 产生并表征在ISR的关键成分中携带人类突变的小鼠，该突变激活了 ISR，并与智力残疾有关。在目标2中，我们将产生和使用最先进的新型分子- 遗传学方法来识别大脑中驱动长期记忆缺陷的特定细胞类型， 激活ISR。最后，在目标3中，我们将开发一种新的高通量筛选平台，以识别新的 ISR的抑制剂。这些目标的结果将为生物学基础提供新的基本见解 认知功能障碍的研究，并希望为认知障碍开辟新的治疗途径， 蛋白质稳态的紊乱

ABSTRACT Cognitive disorders pose a major threat to public health, and represent an enormous economic and social burden. Despite the high incidence of these disorders, effective treatments remain severely limited. Thus, the development of novel therapeutic to treat cognitive disorders is an important goal. Here we focus on the integrated stress response (ISR), a conserved signaling network that restores protein homeostasis by regulating protein synthesis, and a main causative pathway underlying the memory deficits associated with a wide range of cognitive disorders. The goal of this competing renewal is to define the precise molecular, cellular, and circuit mechanisms by which activation of the ISR leads to cognitive dysfunction. In Aim 1, we will generate and characterize mice carrying a human mutation in a key component of the ISR, which activates the ISR, and is associated with intellectual disability. In Aim 2, we will generate and use state-of-the-art, novel molecular- genetic approaches to identify the specific cell types in the brain driving the long-term memory deficits upon activation of the ISR. Finally, in Aim 3, we will develop a novel high-throughput screening platform to identify new inhibitors of the ISR. The results of these Aims will provide new fundamental insights into the biological basis of cognitive dysfunction and hold the hope of opening new therapeutic avenues for cognitive disorders resulting from perturbation of protein homeostasis.