Investigating the role of sleep in brain resilience during aging using a scalable and short-lived vertebrate model

使用可扩展且寿命较短的脊椎动物模型研究睡眠在衰老过程中大脑恢复能力中的作用

• 批准号: 10740068
• 负责人: Ravi Nath
• 金额: $ 12.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740068
• 关键词: Acceleration; Adolescence; Advisory Committees; Affect; African; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animals; Award; Behavior; Behavioral; Biological Models; Biology of Aging; Brain; Brain Diseases; CRISPR/Cas technology; Caffeine; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Consumption; Data Analyses; Dependence; Deterioration; Disease; Drug Modulation; Exhibits; Generations; Genes; Genetic; Gliosis; Goals; Health; Histologic; Histology; Human; Impaired cognition; Inflammation; Institution; Killifishes; Knock-in; Knock-out; Knowledge; Laboratories; Learning; Life; Longevity; Mediating; Melatonin; Memory; Mentors; Methods; Modafinil; Modeling; Molecular Profiling; Monitor; Morbidity - disease rate; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Oxidative Stress; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Proteins; Regulation; Rejuvenation; Research; Risk; Role; Sleep; Sleep Deprivation; Sleep disturbances; Stains; Structure; System; Testing; Time; Training; Universities; Vascular Dementia; Vertebrates; Wakefulness; Waste Products; Western Blotting; Work; age related; aged; aging brain; brain health; career development; circadian; cognitive performance; cognitive testing; cost; experimental study; frailty; genetic manipulation; human data; human old age (65+); improved; improvement on sleep; longitudinal dataset; middle age; neurotoxicity; novel; overexpression; programs; protein aggregation; repaired; resilience; single nucleus RNA-sequencing; skills; sleep behavior; sleep quality; tool; trait; transcriptome sequencing; transcriptomics; β-amyloid burden

Project Summary Sleep is a critical behavioral state that fulfills essential needs for health, including clearing waste products (e.g., amyloid beta [Aβ]) from the brain. As humans age, sleep quality strikingly deteriorates, and this decline correlates with increased risk for neurodegeneration, vascular dementia, and Alzheimer’s disease. While the occurrence of sleep disruption during aging is well documented, the causative impact of sleep on brain resilience with age and disease remains unexplored. I hypothesize that sleep is a key modulator of animal health that can be manipulated to improve brain resilience in the context of aging and disease. To investigate the impact of sleep on brain resilience late in life, I will (Aim 1) characterize if age-associated sleep deterioration (e.g., circadian timing and amount of sleep) impacts cognitive health, (Aim 2) perturb sleep and test the impact on cognitive resilience late in life, and (Aim 3) determine if sleep improves brain resilience in the context of human Aβ1-42 overexpression. The age dependence of sleep deterioration and neurodegeneration is difficult to study at scale due to the time-consuming challenge of aging vertebrates. To overcome this challenge and tackle this question, I will use the African killifish, a model with an extremely short lifespan of only 4-7 months. The killifish exhibits key hallmarks of human aging (e.g., neurodegeneration, frailty) and has conserved brain structures and genes known to regulate sleep. Critically, killifish brains exhibit increases in neurofibrillary degeneration, oxidative stress, gliosis, and inflammation, as well as decreases in repair, as they age. The killifish also possesses practical advantages such as low husbandry costs, a short generation time (<1 month), and genetic tractability. These traits make the killifish a suitable model system to investigate how sleep may impact brain resilience with age. In preliminary efforts, I built a longitudinal tracking system to generate an unprecedented view into how sleep changes across the lifespan, and I found that killifish exhibit an age-associated sleep decline that parallels human sleep decline. I also genetically perturbed sleep and identified novel lifespan-extending genes. I used my new CRISPR knockin method to develop the first killifish model for Alzheimer’s disease. Using these tools and discoveries, I will determine how sleep impacts brain resilience with age and disease. I am pursuing this project at Stanford University with training from my mentor Dr. Anne Brunet, co-mentor Dr. Karl Deisseroth, and an exceptional scientific advisory team whose expertise spans brain aging, Alzheimer’s disease, neurodegeneration, and sleep. Through continued training with the K99/R00 award, I will learn new methods (killifish genetics, intact whole-mount brain staining, and advanced transcriptomic/behavioral data analysis) and concepts (the biology of aging, Alzheimer’s disease, protein aggregation, neurodegeneration). This work, my career development, and my technical training will provide me with the skills and knowledge required to be a successful leader of a laboratory at a top academic institution.

项目摘要 睡眠是满足健康基本需求的关键行为状态，包括清除废物产品（例如， 来自大脑的淀粉样β[Aβ]）。随着人类的年龄，睡眠质量醒目的决定，这种下降 与神经变性，血管痴呆和阿尔茨海默氏病的风险增加有关。而 衰老期间睡眠中断的发生已充分记录，睡眠对大脑的灾难性影响 对年龄和疾病的韧性仍然出乎意料。我假设睡眠是动物的关键调节器 可以在衰老和疾病的背景下进行操纵以改善大脑弹性的健康。调查 睡眠对脑弹性后期的影响，我将（AIM 1）表征是否与年龄相关的睡眠 恶化（例如昼夜节律的时间和睡眠量）会影响认知健康，（目标2）扰动睡眠和 测试对后期认知弹性的影响，（目标3）确定睡眠是否可以提高大脑的弹性 人Aβ1-42过表达的上下文。睡眠定义和神经退行性的年龄依赖性 由于老化脊椎动物的耗时挑战，很难大规模研究。克服这一点 挑战和解决这个问题，我将使用非洲Killifish，这是一个寿命极短的模型 只有4-7个月。 Killifish表现出人类衰老的关键标志（例如，神经变性，脆弱） 保守的大脑结构和已知会调节睡眠的基因。至关重要的是，杀死大脑暴露了 神经原纤维变性，氧化应激，神经胶质和感染以及修复的下降， 年龄。 Killifish还具有实际的优势，例如低饲养成本，短期的时间 （<1个月）和遗传性障碍。这些特征使Killifish成为一个合适的模型系统，以调查如何 睡眠可能会随着年龄的增长而影响大脑的弹性。在初步努力中，我建立了一个纵向跟踪系统 对整个寿命的睡眠变化产生了前所未有的观点，我发现那是杀人的展览 与年龄相关的睡眠下降，与人睡眠的下降平行。我也有基因扰动的睡眠和 确定了新型寿命扩展基因。我使用新的CRISPR敲击方法来开发第一个Killfish 阿尔茨海默氏病的模型。使用这些工具和发现，我将确定睡眠如何影响大脑 与年龄和疾病的韧性。我正在斯坦福大学接受这个项目的培训。 Anne Brunet博士，同事Karl Deisseroth博士和一个杰出的科学咨询团队，其专业知识 跨越大脑衰老，阿尔茨海默氏病，神经退行性病变和睡眠。通过继续培训 K99/R00奖，我将学习新方法（杀死遗传学，完整的全置脑染色和高级 转录组/行为数据分析）和概念（衰老的生物学，阿尔茨海默氏病，蛋白质 聚集，神经变性）。这项工作，我的职业发展以及我的技术培训将为我提供 凭借成为顶级学术机构实验室的成功领导者所需的技能和知识。