Mechanisms of brain rejuvenation

大脑年轻化的机制

• 批准号: 9325394
• 负责人: SAUL A VILLEDA
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325394
• 关键词: Address; Adult; Affect; Aging; Alzheimer' s Disease; Animals; Automobile Driving; Behavioral Paradigm; Bioluminescence; Blood; Brain; Cardiovascular system; Cell physiology; ChIP-seq; Cognitive; Dementia; Elderly; Environment; Event; Exhibits; Exposure to; Functional disorder; Gene Targeting; Genetic Transcription; Health; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Individual; Kinetics; Knowledge; Learning; Left; Mediating; Mediator of activation protein; Memory; Methods; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parabiosis; Pathway interactions; Plasma; Population; Predisposition; RNA Interference; Radial; Rejuvenation; Research; Risk Factors; Role; Signal Transduction; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; Viral; Virus; Water; adult stem cell; age effect; age related; aged; aging brain; aging hippocampus; arm; base; cognitive enhancement; cognitive function; combat; conditioned fear; functional disability; in vivo; insight; mouse model; neurodegenerative phenotype; new therapeutic target; novel strategies; overexpression; synaptic function; synaptogenesis; theories; transcription factor

PROJECT SUMMARY/ABSTRACT Cognitive decline continues to be one of greatest health threats affecting the elderly. In fact, aging remains the single most dominant risk factor for dementia-related neurodegenerative diseases, including Alzheimer's disease. When considering, the rate at which the human population is aging, it becomes imperative to identify means by which to maintain cognitive integrity by protecting against, or even counteracting, the effects of aging. Presupposed dogma holds that the old brain is unable to combat the effects of aging due to a lack of inherent plasticity that facilitates permanent age-related functional impairments. We, and others, have begun to challenge such dogma by showing that systemic manipulations such as heterochronic parabiosis (in which the circulatory systems of young and old animals are connected) can enhance adult stem cell function in the aged brain. Moreover, my lab recently demonstrated that neuronal and cognitive rejuvenation is possible in the aged brain by systemic administration of young blood plasma, and identified the transcription factor Creb as a critical mediator of brain rejuvenation. While the burgeoning field of rejuvenation research is fast growing, the current focus thus far has been placed on identifying individual blood-borne factors in young blood. However, this approach has left fundamental questions unexplored: 1. How long lasting are the rejuvenating effects of young blood on the old brain? 2. What mechanistic changes does young blood elicit in the old brain to promote rejuvenation? 3. Do the beneficial effects of young blood on the aged brain extend to dementia-related neurodegenerative diseases such as Alzheimer's disease? The purpose of the proposed study is thus to investigate the rejuvenating and therapeutic effects of young blood on the aged brain. Specifically, our hypothesis is that systemic exposure to young blood elicits long lasting rejuvenation of synaptic and cognitive functions, while ameliorating neurodegenerative phenotypes. We will test this theory with three Specific Aims: 1. Characterize the kinetics of brain rejuvenation following systemic exposure to young blood. 2. Identify molecular mechanisms downstream of Creb underlying brain rejuvenation by young blood. 3. Distinguish rejuvenating versus therapeutic effects of young blood in a model of accelerated aging and Alzheimer's disease. Ultimately, these studies will challenge traditional views of brain aging by using the rejuvenating effects of young blood to obtain a mechanistic understanding of the cellular events required for unleashing the latent plasticity within the old brain. The results will also have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative diseases such as Alzheimer's disease.

项目摘要/摘要 认知能力下降仍然是影响老年人健康的最大威胁之一。事实上，衰老仍然是 痴呆相关神经退行性疾病（包括阿尔茨海默氏症）的一个最主要的风险因素 疾病当考虑到人口老龄化的速度时， 通过保护或甚至抵消以下影响来保持认知完整性的手段： 衰老预设的教条认为，老年人的大脑是无法对抗老化的影响，由于缺乏 固有的可塑性，促进永久性年龄相关的功能障碍。我们和其他人已经开始 挑战这样的教条，显示系统的操作，如异时共生（其中， 年轻和老年动物的循环系统是相连的）可以增强老年人的成体干细胞功能。 个脑袋此外，我的实验室最近证明，神经元和认知再生在老年人中是可能的。 通过全身给予年轻人血浆，并确定了转录因子Creb作为一个关键的 大脑年轻化的介质。虽然复兴研究的新兴领域正在快速发展，但目前 迄今为止，重点一直放在识别年轻血液中的个体血液传播因子上。但这 这种方法留下了一些基本的问题未被探索：1。年轻人的恢复活力的效果能持续多久 旧大脑上的血2.年轻的血液在年老的大脑中引发了什么样的机械变化， 返老还童？3.年轻血液对老年大脑的有益影响是否延伸到与痴呆症相关的疾病 神经退行性疾病，如阿尔茨海默病？因此，拟议研究的目的是 探讨年轻血液对老年脑的复壮和治疗作用。具体来说，我们 有一种假说认为，全身暴露于年轻血液会使突触和认知神经元持久恢复活力， 功能，同时改善神经退行性表型。我们将用三个具体目标来检验这一理论： 1.描述全身暴露于年轻血液后大脑年轻化的动力学特征。2.识别 Creb下游的分子机制是年轻血液使大脑年轻化的基础。3.区分 在加速老化和阿尔茨海默病模型中年轻血液的恢复与治疗效果 疾病最终，这些研究将挑战传统的大脑衰老观点， 年轻血液的影响，以获得释放所需的细胞事件的机械理解， 老年大脑中潜在的可塑性结果也将具有显著的转化潜力，揭示 可能成为新型疗法的靶点，以改善痴呆相关的神经退行性疾病 老年痴呆症等疾病。