Promoting circadian rhythms to optimize gut-to-brain signaling for Alzheimer's disease

促进昼夜节律，优化阿尔茨海默病的肠道到大脑信号传导

• 批准号: 10717948
• 负责人: Girish C. Melkani
• 金额: $ 186.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717948
• 关键词: Address; Adoption; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Area; Attenuated; Bacteria; Behavior Therapy; Behavioral; Brain; Brain region; Cause of Death; Circadian Dysregulation; Circadian Rhythms; Cognition; Communication; Coupled; Cytology; Dementia; Dietary Intervention; Disease; Disease Progression; Disease model; Drosophila genus; Drosophila melanogaster; Eating; Enterobacteriaceae; Enteroendocrine Cell; Exhibits; Fasting; Food; Food Access; Functional disorder; Gene Expression; Genes; Genetic; Genetic Models; Health; Human; Human Microbiome; Impaired cognition; Inflammation; Inflammatory; Intervention; Kefir; Learning; Light; Link; Lipids; Locomotion; Maintenance; Measures; Mediating; Memory; Metabolic; Metagenomics; Modeling; Molecular; Mushroom Bodies; Nerve; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathology; Pathway interactions; Pattern; Periodicity; Population; Population Heterogeneity; Probiotics; Research; Role; Series; Severities; Signal Transduction; Sleep; Sleep Wake Cycle; Synapses; Synapsins; Testing; Therapeutic; Time; Time Series Analysis; Time-restricted feeding; Tissues; Transgenic Organisms; United States; Vagus nerve structure; Validation; base; beta amyloid pathology; cell type; circadian; circadian behavioral rhythms; disease phenotype; dysbiosis; efficacy evaluation; experimental study; feeding; fly; functional decline; gain of function; genetic manipulation; gut dysbiosis; gut inflammation; gut microbiome; gut microbiota; human microbiota; in vivo; in vivo evaluation; innovation; insight; knock-down; loss of function; microbial; microbiome; microbiome alteration; microbiome analysis; microbiota; neuroinflammation; novel; prevent; probiotic therapy; tau Proteins; tool

Project Summary Alzheimer’s disease (AD) is the leading cause of neurodegeneration worldwide and one of the leading causes of death in the United States. AD patients have reduced gut microbiome population diversity and altered microbiota species composition. However, little is known about the relationship between microbiome alterations and the onset or progression of AD including gut-to-brain signaling. To investigate these interactions, we propose using the well-characterized genetic model of AD, Drosophila melanogaster (fruit fly) to test the impact of genetic or environmental circadian rhythm disruptions (CRD) on the microbiome population, and the onset and severity of the cognitive decline in AD. In our study, we intend to address the effects of dysbiosis on AD progression, and mechanistic aspects of genetic manipulation in specific regions of the nervous system on the microbiota composition for gut-to-brain accesses. Moreover, to restore AD-induced dysbiosis and CRD-mediated metabolic dysregulation, we will impose time-restricted feeding (TRF), an effective behavioral intervention in which food is provided to flies only during the active cycle. The time-series microbiome and metagenomic analyses will be performed under ad lib fed (ALF) and TRF to further recognize the mechanistic basis of microbiome-induced AD. The functional significance of microbiota and altered signaling will be tested in vivo by expressing genetic gain-of-function and loss-of-function approaches. Moreover, probiotics are known to influence human health and will be tested for their impact on fly AD models. Our novel in vivo genetic-transgenic Drosophila disease model coupled with tissue-specific functional, cytological metabolic, and microbiomes will generate unbiased/mechanistic insights into gut-to-brain signaling for AD. The following aims will be used to test our hypothesis and explore the role of the microbiome in AD, including factors that optimized AD that mitigates dysbiosis. 1. Determine whether depletion of gut microbiota results in AD-induced neurodegeneration and TRF retain healthy microbiome in humanized Drosophila AD models. 2. Determine how dysbiosis-induced gut-to-brain signaling occurs in Drosophila models of AD. 3. Time-series analysis of Drosophila microbiome in AD model under ALF and TRF, and their validation in vivo, including testing human microbiome and probiotic for therapeutic treatments. Successful completion of this project will provide a deeper molecular understanding of the microbiome association in promoting circadian rhythm via TRF-optimized gut-to-brain signaling for AD. Overall, our complementary and innovative approaches are suitable for PAR-22-211 and will address the molecular basis of dysbiosis in AD and dysmetabolism TRF is beneficial in the context of AD by promoting circadian rhythms and a healthy microbiome, along with also evaluating therapeutic probiotic treatments. Additionally, this research will assess the efficacy of a behavioral intervention that would have a high potential for adoption in humans.

项目概要 阿尔茨海默病 (AD) 是全世界神经退行性疾病的主要原因，也是主要原因之一 美国 AD 患者的肠道微生物群多样性降低， 然而，人们对微生物组变化之间的关系知之甚少。 以及 AD 的发作或进展，包括肠道到大脑的信号传导，我们建议研究这些相互作用。 使用 AD 的良好表征的遗传模型，黑腹果蝇（果蝇）来测试遗传的影响 或环境昼夜节律紊乱（CRD）对微生物群的影响，以及其发生和严重程度 在我们的研究中，我们打算解决生态失调对 AD 进展的影响，以及 神经系统特定的基因操作对微生物群的机械区域方面 用于肠道到大脑通路的组合物。 此外，为了恢复 AD 引起的生态失调和 CRD 介导的代谢失调，我们将强加 限时喂食（TRF），一种有效的行为干预措施，仅在 时间序列微生物组和宏基因组分析将在自由喂养（ALF）下进行。 和 TRF 进一步认识微生物组诱发 AD 的机制基础和功能意义。 将通过表达遗传功能获得和功能丧失来测试微生物群和改变的信号传导 此外，已知益生菌会影响人类健康，并将测试其对苍蝇的影响。 AD 模型。我们的新型体内转基因果蝇疾病模型与组织特异性相结合。 功能、细胞学代谢和微生物组将对肠道到大脑产生公正/机械的见解 以下目标将用于检验我们的假设并探索微生物组的作用。 AD，包括优化 AD 以减轻生态失调的因素。 1. 确定肠道微生物群的消耗是否会导致 AD 诱导的神经变性和 TRF 在人源化果蝇 AD 模型中保留健康的微生物组。 2. 确定 AD 果蝇模型中生态失调诱导的肠道到大脑信号传导是如何发生的。 3. ALF和TRF下AD模型中果蝇微生物组的时间序列分析及其验证 体内，包括测试人体微生物组和益生菌的治疗效果。 该项目的成功完成将提供对微生物组更深入的分子了解 通过 TRF 优化的肠道到大脑信号传导促进 AD 的昼夜节律的关联。 补充和创新方法适用于 PAR-22-211，并将解决以下问题的分子基础： AD 中的生态失调和代谢障碍 TRF 通过促进昼夜节律和 此外，这项研究还将评估健康的微生物组。 评估行为干预的有效性，该行为干预在人类中具有很高的应用潜力。