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

以慢波睡眠为目标来控制神经元活动和β-淀粉样蛋白动态

• 批准号: 9298744
• 负责人: Yo-El S Ju
• 金额: $ 17.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298744
• 关键词: Acceleration; Affect; Aftercare; Age; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid beta-Protein; Auditory; Award; Brain; Cerebrospinal Fluid; Chronic; Circadian Rhythms; Clinical; Cognitive; Data; Dementia; Deposition; Disease Progression; Education; Elderly; Electroencephalogram; Electrophysiology (science); Ensure; Ethics; Event; Experimental Models; Foundations; Frequencies; Goals; Human; Impaired cognition; Individual; Intercellular Fluid; Lead; Life; Link; Measurable; Measurement; Measures; Medicine; Mentors; Methods; Modeling; Neurodegenerative Disorders; Neurons; Obstructive Sleep Apnea; Pathogenesis; Pathologic; Physicians; Population; Population Study; Prevalence; Principal Investigator; Procedures; Professional Competence; Protocols documentation; Public Health; Research; Resources; Rest; Risk; Safety; Scientist; Senile Plaques; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Stages; Sleep Wake Cycle; Sleep disturbances; Slow-Wave Sleep; Spinal Puncture; Supervision; Synapses; Techniques; Testing; Training; Translating; Universities; Wakefulness; Washington; abeta accumulation; career; didactic education; effective therapy; experience; experimental study; human study; improved; interstitial; middle age; mouse model; multidisciplinary; novel; pressure; prevent; public health relevance; responsible research conduct; signal processing; treatment effect

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.

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，这一数字还会增加。睡眠障碍与 AD 的大脑变化有关，甚至早于认知问题。在小鼠模型中，睡眠不足会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，睡眠障碍会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，导致间质内单体淀粉样蛋白 (Aβ) 释放相对增加，导致 Aβ 水平长期升高，导致 Aβ 聚集成淀粉样蛋白斑块的风险增加，最终导致出现症状的风险增加 公元。该项目将通过使用两种不同的模型检查 SWS 和 A β 水平的关系来测试这一假设级联的第一部分：1）一个实验模型，其中正常个体的 SWS 受到干扰；2）一个临床模型，其中患有阻塞性睡眠呼吸暂停（一种扰乱睡眠的常见睡眠障碍）的人将在治疗前后测试 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 AD 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颖方案的培训之外，首席研究员还将在获奖过程中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，以确保其以安全和道德的方式完成，并将支持负责任的研究行为的持续教育。由世界一流的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物质资源，将优化培训经验和成功过渡到独立研究的可能性。在此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叉点的医生科学家开启成功的职业生涯。