Optimized Circadian Rhythms for the Prevention of Alzheimer's Disease

优化昼夜节律以预防阿尔茨海默病

• 批准号: 10037591
• 负责人: Girish C. Melkani
• 金额: $ 304.6万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10037591
• 关键词: Address; Adoption; Affect; Age; Aging; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-42; Animals; Attenuated; Behavior Therapy; Biological Process; Brain; Caloric Restriction; Candidate Disease Gene; Cardiac; Cell physiology; Chronic; Chronic Disease; Circadian Dysregulation; Circadian Rhythms; Competence; Consumption; Coupled; Disease; Disease model; Drosophila genus; Drosophila melanogaster; Eating; Energy Intake; Exhibits; Eye; Food; Genes; Genetic; Genetic Models; Genetic Risk; Geroscience; Harvest; Head; Hour; Human; Intervention; Light; Locomotion; Longevity; Measures; Mediating; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Chaperones; Molecular Profiling; Monitor; Muscle function; Mutation; Myocardium; Neurons; Onset of illness; Organ; Pathology; Pathway interactions; Pattern; Performance; Peripheral; Phenotype; Process; Production; RNA; Research; Rest; Risk; Risk Factors; Role; Series; Severities; Severity of illness; Sleep; Sleep Wake Cycle; Techniques; Testing; Time; Time-restricted feeding; Tissues; Transcript; Transgenic Organisms; age related; chaperonin CCT; circadian; circadian behavioral rhythms; circadian pacemaker; cohort; differential expression; disease phenotype; experimental study; feeding; fly; functional decline; gain of function; heart function; in vivo; insight; loss of function; loss of function mutation; mutant; nervous system disorder; novel; protective effect; protein folding; relating to nervous system; repaired; tau Proteins; tool; transcriptome

Geroscience hypothesis posits that aging itself is the underlying major risk factor for age-related chronic diseases, including Alzheimer's Disease (AD); therefore, delaying aging delays disease, including AD. This proposal will examine the reciprocal relationship between circadian rhythm disruption (CRD) and AD pathology. Circadian rhythms, which are intimately interlinked with cellular metabolism, orchestrate the coordinated expression and function of multiple pathways that support normal cellular function and repair in both neural and peripheral tissues. Circadian rhythms deteriorate with aging, and Alzheimer's patients show disrupted circadian rhythm. However, the causal role of CRD for AD is not clear. The proposal will assess the relationship between circadian rhythm disruption and AD pathology, will test whether improvement in circadian rhythms delay the onset and progression of AD. and will attempt to identify underlying molecular mechanisms. Well-characterized Drosophila melanogaster (fruit fly) models of AD with Drosophila genetic tools will be used to test the impact of genetic or environmental CRD on the onset and severity of the multiorgan functional decline in AD. One feature of CRD is the lack of feeding consolidation to daylight hours in diurnal animals. To restore aspects of circadian rhythm in older flies, animals will be subject to time-restricted feeding (TRF) in which food is provided to flies only during the 12 h day time. TRF does not reduce daily caloric intake and imparts a molecular signature that is distinct from that under caloric restriction. Disease onset and severity will be assessed in TRF, and ad lib fed (ALF) flies to determine if TRF is an effective behavioral intervention for AD. To test the molecular pathways mediating the opposite effects of CRD and TRF on AD pathologies, time-series transcriptomes from these flies will be analyzed to find candidate pathways. The functional significance of these pathways will be tested by expressing genetic gain of function and loss of function alleles in AD flies. Our novel in vivo genetic-transgenic Drosophila disease model coupled with ultrastructural, functional, metabolic, and transcriptome techniques will generate unbiased insights into the mechanistic basis of accelerated aging in production of AD. Successful completion of this project will provide a deeper molecular understanding of the interaction between circadian rhythm and genetic risk of AD. Additionally, this research will assess the efficacy of a behavioral intervention that would have a high potential for adoption in humans.

老年科学假说认为，衰老本身是老年痴呆症的潜在主要风险因素。 与年龄相关的慢性疾病，包括阿尔茨海默病（AD）;因此， 衰老延缓疾病，包括AD。这项建议将审查互惠关系 昼夜节律紊乱（CRD）和AD病理之间的关系。昼夜节律， 与细胞代谢密切相关，协调表达 支持正常细胞功能和修复的多种途径的功能， 和外周组织。昼夜节律随着年龄的增长而恶化，老年痴呆症患者表现出 打乱了昼夜节律然而，CRD对AD的因果作用尚不清楚。该提案将 评估昼夜节律破坏和AD病理之间的关系，将测试是否 昼夜节律的改善延迟AD的发作和进展。并且将尝试 确定潜在的分子机制。 用果蝇遗传工具充分表征的AD果蝇（果蝇）模型 将被用来测试遗传或环境CRD的发病和严重程度的影响， AD患者多器官功能下降。CRD的一个特点是缺乏饲料巩固， 白天活动的动物。为了恢复老年果蝇的昼夜节律， 将受到时间限制喂养（TRF），其中食物仅在 12小时白天时间。TRF不减少每日热量摄入，并赋予一种分子特征， 与限制热量摄入的情况不同。将在TRF中评估疾病发作和严重程度， 和自由进食（ALF）苍蝇，以确定是否TRF是一种有效的行为干预AD。到 测试介导CRD和TRF对AD病理学的相反作用的分子途径， 将分析来自这些果蝇的时间序列转录组以发现候选途径。的 这些途径的功能意义将通过表达功能的遗传获得来测试， AD果蝇中功能等位基因的丢失。我们新的体内遗传转基因果蝇疾病 模型结合超微结构、功能、代谢和转录组技术， 对AD生产中加速老化的机理基础产生公正的见解。 该项目的成功完成将提供更深入的分子理解， 昼夜节律与AD遗传风险相互作用此外，这项研究 将评估行为干预的有效性，这将有很高的潜力， 人类的收养。