Elucidating the role of circadian-gated cognitive disruption in Alzheimer’s disease pathogenesis

阐明昼夜节律门控认知破坏在阿尔茨海默病发病机制中的作用

• 批准号: 10450631
• 负责人: Anisha Kalidindi
• 金额: $ 3.56万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450631
• 关键词: Activity Cycles; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid deposition; Automobile Driving; Award; Behavioral; Biochemical; Biology; Brain; Cause of Death; Cell physiology; Cephalic; Circadian Dysregulation; Cognition; Cognitive; Cognitive deficits; Complement; Confusion; Data; Deterioration; Diagnostic; Disease; Drug Delivery Systems; Elderly; Etiology; Fellowship; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic study; Goals; Health; Hormones; Hour; Human; Image; Immunofluorescence Immunologic; Impaired cognition; Lead; Learning; Life Expectancy; Light; Link; Measures; Mediating; Memory; Mentors; Mitogen-Activated Protein Kinases; Modality; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Output; Pathogenesis; Pathway interactions; Pattern; Periodicity; Phase; Phosphotransferases; Physiology; Population; Positioning Attribute; Process; Protein Analysis; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Resolution; Role; Scientist; Shapes; Sleep; Sleep Disorders; Sleep disturbances; System; Testing; Time; Training; Work; aging population; behavior test; career; circadian; circadian regulation; cognitive ability; common symptom; human old age (65+); in vivo; innovation; knowledge base; mouse model; multiphoton imaging; professor; restoration; skills; sleep physiology; temporal measurement; tool

Project Abstract As the portion of the population that is aged 65 and older rapidly increases in parallel with increases in life expectancy, there is an urgent need to address the disease states that affect the elderly population. One of these—perhaps the most devastating—is Alzheimer’s disease (AD). In addition to the cognitive impairments that underlie AD, these patients suffer with dysregulation of their circadian timing system including cognition. This timing system is vital to health at the cellular level and to overall physiology; hence, circadian disruptions can have profound negative effects on health, further exacerbating the AD symptomology. Specifically, circadian- gated cognition is the inherent 24-hour cycles of regulation that underlie efficacy of learning and memory across the day. Along these lines, the goal of this work is to better understand the molecular components in the brain that mediate deterioration of circadian-gated cognition in AD. Utilizing an innovative set of approaches ranging from behavioral testing to in vivo cranial window multiphoton imaging, this work will address the following specific aims. My dissertation work thus far (Aim 1) has shown that circadian-gated cognitive deficits are present in a mouse model of rapid amyloid deposition and that there are disruptionin core clock genes that generate circadian timing may mediate these. Circadian timing regulates a plethora of cellular processes, including the functionality of the mitogen activated protein kinase (MAPK) pathway. Furthermore, the MAPK pathway is essential to circadian-gated cognitiveprocesses and its activation has been shown to be disrupted in AD. Thus, in next phase of my work (F99, Aim 2), I will test if the dysregulation of MAPK pathway activation is the mechanistic link governing disruption of circadian-gated cognition in a model of AD. In addition to profiling the disruption of MAPK activity in AD, I will attempt to restore activity of the MAPK pathway to baseline, thus rescuing circadian-gated cognition. Upon the completion of my dissertation work, I plan to complete a postdoctoral fellowship (K00, Aim 3) where I will aim to study the genetic basis of sleep in parallel with the genetic mechanisms underlying sleep dysfunction in neurodegenerative disorders. This postdoctoral work will complement my training in circadian biology and neurodegeneration ultimately providing me the necessary tools and skill to address questions regarding the interplay of sleep and circadian rhythmicity disruption in neurodegenerative.

项目摘要 由于65岁及以上的人口比例随着寿命的增加而迅速增加， 除了预期之外，迫切需要解决影响老年人口的疾病状况。之一 这些-也许是最令人不安的-是阿尔茨海默氏病（AD）。除了认知障碍， 作为AD的基础，这些患者患有包括认知在内的昼夜节律计时系统的失调。这 生物钟系统在细胞水平和整体生理学上对健康至关重要;因此，昼夜节律中断可以 对健康有深远的负面影响，进一步加剧了AD的发病率。具体来说，昼夜- 门控认知是内在的24小时调节周期，是学习和记忆功效的基础。 白天沿着这些线索，这项工作的目标是更好地了解大脑中的分子组成部分 介导AD中昼夜节律门控认知的恶化。利用一套创新的方法， 从行为测试到活体颅窗多光子成像，这项工作将解决以下具体问题 目标。到目前为止，我的论文工作（目标1）表明，昼夜节律门控认知缺陷存在于一个 快速淀粉样蛋白沉积的小鼠模型，以及产生昼夜节律的核心时钟基因的破坏 时间可以调解这些。昼夜节律调节了大量的细胞过程，包括功能性 丝裂原活化蛋白激酶（MAPK）通路。此外，MAPK通路对于 昼夜节律门控的认知过程及其激活在AD中被破坏。因此，在下一阶段 在我的工作（F99，目标2）中，我将测试MAPK通路激活的失调是否是 在AD模型中控制昼夜节律门控认知的中断。除了分析MAPK的破坏之外， 活动在AD，我将试图恢复活性的MAPK途径的基线，从而挽救昼夜节律门控 认知.在完成我的论文工作后，我计划完成博士后奖学金（K 00，Aim 3)在那里，我将致力于研究睡眠的遗传基础， 神经退行性疾病中的功能障碍。这项博士后工作将补充我在昼夜节律方面的训练 生物学和神经退行性变最终为我提供了必要的工具和技能来解决问题 关于睡眠和昼夜节律破坏在神经退行性疾病中的相互作用。