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.

项目摘要 阿尔茨海默病（AD）是世界范围内神经退行性疾病的主要原因，也是导致阿尔茨海默病的主要原因之一。 死亡在美国。AD患者的肠道微生物群落多样性降低， 微生物群物种组成。然而，人们对微生物组改变之间的关系知之甚少。 以及AD的发作或进展，包括肠-脑信号传导。为了研究这些相互作用，我们建议 使用AD的良好表征的遗传模型，果蝇（果蝇）来测试遗传因素的影响， 或环境昼夜节律中断（CRD）对微生物组的影响，以及 AD认知能力下降的原因。在我们的研究中，我们打算解决生态失调对AD进展的影响， 神经系统特定区域的遗传操作对微生物群的机制方面 用于肠到脑通路的组合物。 此外，为了恢复AD诱导的生态失调和CRD介导的代谢失调，我们将实施 时间限制喂养（TRF），一种有效的行为干预，其中仅在 活跃的周期。时间序列微生物组和宏基因组分析将在自由进食（ALF）下进行。 和TRF进一步认识微生物群诱导的AD的机制基础。的功能意义 微生物群和改变的信号传导将通过表达遗传功能获得和功能丧失来在体内进行测试。 接近。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。我们的新的体内遗传转基因果蝇疾病模型加上组织特异性 功能、细胞代谢和微生物组将产生对肠到脑的无偏见/机制的见解 AD的信号。以下目标将用于验证我们的假设并探索微生物组的作用 在AD中，包括优化缓解生态失调的AD的因素。 1.确定肠道微生物群的消耗是否会导致AD诱导的神经退行性变和TRF 在人源化果蝇AD模型中保留健康的微生物组。 2.确定在AD的果蝇模型中生态失调诱导的肠道到大脑的信号传导是如何发生的。 3. ALF和TRF下AD模型果蝇微生物群的时间序列分析及其验证 在体内，包括测试人类微生物组和益生菌用于治疗性治疗。 该项目的成功完成将为微生物组提供更深入的分子理解 通过TRF优化的AD肠-脑信号传导促进昼夜节律的关联。总体而言，我们 补充和创新的方法适用于PAR-22-211，并将解决PAR-22 - 211的分子基础。 AD中的生态失调和代谢失调TRF通过促进昼夜节律在AD的背景下是有益的， 健康的微生物组，沿着还有评估治疗性益生菌治疗。此外，这项研究将 评估行为干预的有效性，这将有很大的潜力在人类中采用。