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），随着人口老龄化，这一数字预计还会增加。睡眠障碍与阿尔茨海默病的大脑变化有关，甚至比认知问题更早。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应用于人类。这项人类研究的主要假设是，睡眠障碍导致深度睡眠或慢波睡眠（SWS）减少，导致神经元突触活性相对增加，导致单体淀粉样蛋白- β (A β)释放到间质空间相对增加，导致A β水平长期升高，导致A β聚集成淀粉样斑块的风险增加，最终导致症状性AD的风险增加。该项目将通过使用两种不同的模型来检查SWS和A β水平的关系来测试这个假设级联的第一部分：1)一个实验模型，在这个模型中，正常个体的SWS被破坏；2)一个临床模型，在这个模型中，患有阻塞性睡眠呼吸暂停（一种常见的睡眠障碍，会干扰睡眠）的人在治疗前后测试SWS和A β水平。这一系列研究的长期目标是确定是否可以改变或改善睡眠，以降低患阿尔茨海默病的风险。该项目的研究团队结合了睡眠医学、AD和电生理学方面的专业知识。除了为研究实验提出的技术和新协议方面的培训外，首席研究员还将在获奖期间获得信号处理方面的正式教学教育。安全咨询小组将监督拟议的研究，以确保其以安全和合乎道德的方式完成，并将支持正在进行的负责任的研究行为教育。由世界级导师和合作者组成的多学科团队，以及华盛顿大学广泛的智力和物质资源，将优化培训经验，并提高成功过渡到独立研究的可能性。在此奖项中获得的技术，研究和职业技能将促进首席研究员作为一名研究睡眠和神经退行性疾病交叉的医生科学家的成功职业生涯。

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.