TARGETING SLOW WAVE SLEEP TO CONTROL NEURONAL ACTIVITY AND AMYLOID-BETA DYNAMICS

描述(由申请人提供)：目前有超过500万美国人患有阿尔茨海默病(AD)，预计随着人口老龄化，这个数字还会增加。睡眠障碍与阿尔茨海默病的大脑变化有关，甚至在认知问题之前就是如此。在小鼠模型中，睡眠剥夺导致淀粉样斑块沉积加速，这是AD的一个关键病理特征。拟议中的项目将把这一发现转化为人类。这项人类研究的总体假设是，睡眠障碍导致深度睡眠或慢波睡眠(SWS)减少，导致神经元突触活动相对增加，导致单体淀粉样β(Aβ)释放到间质间隙，导致Aβ水平长期升高，导致Aβ聚集到淀粉样斑块的风险增加，最终导致症状性AD风险增加。该项目将通过使用两种不同的模型来检验SWS和Aβ水平的关系，以检验这一假想串联的第一部分：1)在实验模型中，SWS在正常人中受到干扰；2)在临床模型中，患有阻塞性睡眠呼吸暂停的人将在治疗前后检测SWS和Aβ水平。阻塞性睡眠呼吸暂停是一种常见的睡眠障碍。这项研究的长期目标是确定是否可以修改或改善睡眠，以降低AD的风险。这个项目的研究团队结合了睡眠医学、AD和电生理学的专业知识。除了为研究性实验建议的技术和新方案的培训外，首席调查员还将在获奖过程中获得信号处理方面的正式教学教育。一个安全咨询小组将监督拟议的研究，以确保以安全和合乎道德的方式完成研究，并将支持对负责任的研究进行持续的教育。由世界级导师和合作者组成的多学科团队，以及华盛顿大学丰富的智力和体力资源，将使培训体验和成功过渡到独立研究的可能性得到优化。在该奖项期间获得的技术、研究和职业技能将有助于首席研究员作为一名研究睡眠和神经退行性疾病交集的内科科学家开始成功的职业生涯。

DESCRIPTION (provided by applicant): Over 5 million Americans currently suffer from Alzheimer Disease (AD), a number predicted to increase as the population ages. Sleep disturbances are associated with brain changes of AD, even before cognitive problems. In mouse models, sleep deprivation leads to acceleration of amyloid plaque deposition, a key pathological feature of AD. The proposed project will translate this finding to humans. The overarching hypothesis for this human study is that sleep disturbance leads to decreased deep sleep or slow wave sleep (SWS), leading to relatively increased neuronal synaptic activity, leading to relatively increased monomeric amyloid-beta (A beta) release into the interstitial space, leading to chronically elevated A beta levels, leading to increased risk of aggregation of A beta into amyloid plaques, and eventually leading to increased risk of symptomatic AD. This project will test the first portion of this hypothetical cascade by examining the relationship of SWS and A beta levels using two different models: 1) An experimental model in which SWS is disrupted in normal individuals and, 2) a clinical model in which people with obstructive sleep apnea, a common sleep disorder that disrupts sleep, will have SWS and A beta levels tested before and after treatment. The long-term objective of this line of research is to determine whether sleep can be modified or improved with the goal of reducing risk of AD. The research team for this project combines expertise in sleep medicine, AD, and electrophysiology. In addition to training in the techniques and novel protocols proposed for the research experiments, the Principal Investigator will obtain formal didactic education in signal processing over the course of the award. A Safety Advisory Panel will supervise the proposed study to ensure it is completed in a safe and ethical manner, and will buttress ongoing education in the responsible conduct of research. The multidisciplinary team of world-class mentors and collaborators, and the extensive intellectual and physical resources available at Washington University, will optimize the training experience and the likelihood for successful transition to independent research. The technical, research, and career skills obtained during this award will facilitate the Principal Investigator in launching a successful career as a physician-scientist investigating the intersection of sleep and neurodegenerative diseases.