Systems Genetics Analysis of Alzheimer's Disease-Related Sleep Loss and the Transition to Dementia

项目摘要 我们提出的研究有望确定与睡眠障碍相关的遗传因素， 阿尔茨海默病（AD），并确定他们是否可以干预，以避免认知症状。检测 这些基因的验证将通过发现新的靶点和生物学效应来促进可能的治疗。 可能有助于减轻疾病负担和改善人类生活质量的途径。数据 本提案中生成的数据也将与来自人类队列的可用数据集进行交叉检查， 死后样本，这样的进步，我们目前的网络和机制的理解， 可以在人AD的背景下理解小鼠。我们将利用先进的小鼠模型， 识别 分子和细胞机制之间的双向关系AD病理和 睡眠中断。在目标1中，我们将识别与睡眠不足相关的基因和分子网络， 更好地模拟人类AD的大群AD小鼠。在目标2中，我们将翻译基因和网络 睡眠丧失与人类AD队列的潜在差异。最后，在目标3中，我们将验证遗传和 与睡眠丧失和功能障碍相关的可变因素，并确定其对发病和 在强大的AD模型中记忆缺陷的进展。

PROJECT SUMMARY Our proposed research is expected to identify genetic factors that underlie disordered sleep associated with Alzheimer's disease (AD), and determine if they are intervenable to stave off cognitive symptoms. Detection and validation of these genes will promote possible treatments through discovery of new targets and biological pathways that may aid in alleviating disease burden and improving quality of life in humans. The data generated in this proposal will also be cross-checked with available datasets from human cohorts and postmortem samples, such that advances in our current understanding of the networks and mechanisms in mice can be understood in the context of human AD. We will leverage advanced mouse models to identify molecular and cellular mechanisms underlying the bidirectional relationship between AD pathology and disruptions in sleep. In Aim 1, we will identify genes and molecular networks associated with sleep loss in a large population of AD mice that better model human AD. In Aim 2, we will translate genes and networks underlying variation in sleep loss to human AD cohorts. Finally, in Aim 3, we will validate genetic and modifiable factors associated with sleep loss and dysfunction, and determine their effects on onset and progression of memory deficits in powerful AD models.