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 睡眠是一种关键的行为状态，可以满足健康的基本需求，包括清除废物（例如， 淀粉样蛋白β [A β]）。随着人类年龄的增长，睡眠质量显著恶化，这种下降 与神经变性、血管性痴呆和阿尔茨海默病的风险增加相关。而 睡眠中断在衰老过程中的发生是有据可查的，睡眠对大脑的因果影响 对年龄和疾病的适应能力仍未得到探索。我假设睡眠是动物 健康可以被操纵，以提高大脑在衰老和疾病的背景下的弹性。探讨 睡眠对晚年大脑恢复力的影响，我将（目标1）描述与年龄相关的睡眠 恶化（例如，昼夜节律时间和睡眠量）影响认知健康，（目的2）扰乱睡眠， 测试对晚年认知恢复力的影响，并（目标3）确定睡眠是否能改善老年人的大脑恢复力。 人A β 1 - 42过表达的背景。睡眠恶化和神经退行性变的年龄依赖性 由于老化脊椎动物的挑战很耗时，因此很难大规模研究。为了克服这个 挑战和解决这个问题，我将使用非洲鳉鱼，一种寿命极短的模型， 只有4 - 7个月。鳉鱼表现出人类衰老的关键特征（例如，神经变性，虚弱）， 保守的大脑结构和已知的调节睡眠的基因。重要的是， 神经退行性变、氧化应激、神经胶质增生和炎症，以及修复减少，因为它们 年龄鳉鱼还具有养殖成本低、世代时间短等实用优势 （<1个月）和遗传易处理性。这些特征使鳉鱼成为一个合适的模型系统，以研究如何 睡眠可能会随着年龄的增长而影响大脑的弹性。在初步的努力中，我建立了一个纵向跟踪系统， 对睡眠在人的一生中是如何变化的产生了前所未有的看法，我发现， 一种与年龄相关的睡眠下降，与人类睡眠下降相似。我也遗传性地扰乱睡眠， 发现了新的延长寿命的基因。我用我的新CRISPR敲入方法培育了第一条 阿尔茨海默病的模型。利用这些工具和发现，我将确定睡眠如何影响大脑 抵抗年龄和疾病的能力我正在斯坦福大学从事这个项目，并接受我导师的培训 博士Anne Brunet，共同导师Karl Deisseroth博士，以及一个杰出的科学顾问团队， 涵盖了大脑老化、阿尔茨海默病、神经退化和睡眠。通过继续培训， K99/R00奖，我将学习新的方法（鱼遗传学，完整的全脑染色，和先进的 转录组学/行为数据分析）和概念（衰老生物学、阿尔茨海默病、蛋白质 聚集、神经变性）。这项工作，我的职业发展，我的技术培训将为我提供 拥有成为顶尖学术机构实验室成功领导者所需的技能和知识。