Dark GPCR signaling underlying the Microbiome-Gut-Brain Axis for Alzheimer's Disease and Related Dementia

阿尔茨海默病和相关痴呆症微生物组-肠-脑轴的暗 GPCR 信号传导

• 批准号: 10719150
• 负责人: Jonathan Mark Brown
• 金额: $ 234.43万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-18 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719150
• 关键词: Acids; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; American; Amyloid beta-42; Amyloidosis; Astrocytes; Behavior; Binding; Biological; Biological Assay; Biological Markers; Cell Line; Cells; Cerebrum; Clinic; Clinical; Cognitive; Consensus; Cyclic AMP; Darkness; Data; Dementia; Diet; Disease; Disease Progression; Family; Fatty Acids; Functional disorder; Funding; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GPR84 gene; Genes; Genome; Genomic approach; Genomics; Genotype; Germ-Free; Goals; Health; Hippocampus; Human; Human Genome; Individual; Induced pluripotent stem cell derived neurons; Intervention; Mediating; Medium chain fatty acid; Microglia; Modeling; Modification; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nevada; Organoids; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Plasma; Play; Prevention; Prevention strategy; Process; Production; Research; Rodent Model; Role; Sampling; Signal Transduction; Synapses; System; Technology; Testing; United States; United States National Institutes of Health; beta-arrestin; biomarker discovery; candidate identification; clinically relevant; druggable target; effective therapy; epigenomics; experimental study; fecal transplantation; gut microbiome; gut microbiota; gut-brain axis; human subject; improved; induced pluripotent stem cell; innovation; interdisciplinary approach; metabolomics; microbial; microbiome; microbiota metabolites; mild cognitive impairment; mouse model; multimodality; multiple omics; neuroinflammation; predictive modeling; prevent; programs; release of sequestered calcium ion into cytoplasm; screening; sex; stem cell model; targeted treatment; tau aggregation; tau-1; treatment strategy; Acids; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; American; Amyloid beta-42; Amyloidosis; Astrocytes; Behavior; Binding; Biological; Biological Assay; Biological Markers; Cell Line; Cells; Cerebrum; Clinic; Clinical; Cognitive; Consensus; Cyclic AMP; Darkness; Data; Dementia; Diet; Disease; Disease Progression; Family; Fatty Acids; Functional disorder; Funding; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GPR84 gene; Genes; Genome; Genomic approach; Genomics; Genotype; Germ-Free; Goals; Health; Hippocampus; Human; Human Genome; Individual; Induced pluripotent stem cell derived neurons; Intervention; Mediating; Medium chain fatty acid; Microglia; Modeling; Modification; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nevada; Organoids; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Plasma; Play; Prevention; Prevention strategy; Process; Production; Research; Rodent Model; Role; Sampling; Signal Transduction; Synapses; System; Technology; Testing; United States; United States National Institutes of Health; beta-arrestin; biomarker discovery; candidate identification; clinically relevant; druggable target; effective therapy; epigenomics; experimental study; fecal transplantation; gut microbiome; gut microbiota; gut-brain axis; human subject; improved; induced pluripotent stem cell; innovation; interdisciplinary approach; metabolomics; microbial; microbiome; microbiota metabolites; mild cognitive impairment; mouse model; multimodality; multiple omics; neuroinflammation; predictive modeling; prevent; programs; release of sequestered calcium ion into cytoplasm; screening; sex; stem cell model; targeted treatment; tau aggregation; tau-1; treatment strategy

PROJECT SUMMARY Cumulative evidence indicates the Microbiome-Gut-Brain axis plays a crucial role in Alzheimer’s disease (AD) and supports the potential of microbiome-targeted therapies as treatments for AD and AD-related dementia (ADRD). However, the precise mechanism of the Microbiome-Gut-Brain axis and the identity of actionable gut microbial biomarkers underlying AD/ADRD pathogenesis, disease progression, and modification remind understudied. Recent advances in chemogenomic technologies have demonstrated that G-protein-coupled receptors (GPCRs, the largest druggable target family in the human genome, as defined by the NIH-funded Illuminating the Druggable Genome Program) mediate much of the Microbiome-Gut-Brain axis, especially for gut microbiota-derived metabolites such as medium-chain fatty acids (MCFAs). Our preliminary experiments reveal strong significant associations between gut-microbiota MCFA metabolites (e.g., 5-phenylvaleric acid) and dark GPCR signaling (e.g., GPR84) in AD using multi-omics approaches and an AD patient-induced pluripotent stem cells (iPSC) model. Furthermore, we identified targeting gut microbial metabolite pathways improve cognitive behaviors in germ-free mice. We posit that combining AD patient-induced iPSC, cerebral organoids, and germ-free mouse models, along with multimodal analyses of plasma and hippocampus gut microbial metabolomics data, will enable improved mechanistic understanding of precise protective mechanisms of the Microbiome-Gut-Brain axis in AD/ADRD. Our central unifying hypothesis is that identifying likely molecular drivers (e.g., gut microbial metabolites) and druggable GPCR signaling networks underlying the Microbiome- Gut-Brain axis will elicit potential prevention and treatment strategies for AD. Aim 1 will test dark GPR84 (a putative microglial gene) and its signaling activation underlying the Microbiome-Gut-Brain axis of MCFAs via fecal microbiota transplantation (FMT) in germ-free mice by assessing AD-related cognitive and pathological phenotypes and mechanisms. We will evaluate differential gut microbial communities, untargeted and targeted gut metabolomics analyses of plasma and hippocampus in GPR84-/-, 5xFAD, and cross (5xFAD;GPR84-/-) germ-free mice during pre-FMT and post-FMT. Aim 2 will screen, test and validate dark GPCRs and signaling network perturbation by gut microbiota-derived MCFA metabolites using AD patient-derived iPSC lines in conjunction with cerebral organoid models. Specifically, we will evaluate physical binding of the gut microbial metabolite-GPCR interactome using complementary Calcium flux, cAMP glosensor, and β-arrestin Tango assays. Aim 3 will conduct supervised analyses of gut microbial metabolite biomarker discovery for, and prediction modeling of, clinically relevant AD pathological features using patient plasma targeted and untargeted gut microbial metabolomics. In summary, our multidisciplinary approach comprising germ-free mice, AD patient- derived iPSC, and cerebral organoid models, along with human plasma gut microbial metabolomics, will identify potential microbiome-targeted prevention and treatment approaches to be directly tested in people with AD.

项目摘要 累积证据表明，微生物组脑轴在阿尔茨海默氏病中起着至关重要的作用 （AD）并支持微生物组靶向疗法的潜力作为AD和AD相关痴呆的疗法 （ADRD）。但是，微生物组 - 脑轴的精确机制和可起作的肠道身份 AD/ADRD发病机理，疾病进展和修饰的微生物生物标志物提醒 研究了。化学生成技术的最新进展表明，G蛋白偶联 受体（GPCR是人类基因组中最大的可药物靶标家族，由NIH资助 照亮可毒的基因组计划）介导了许多微生物组甲状脑轴，尤其是针对 肠道菌群衍生的代谢产物，例如中链脂肪酸（MCFAS）。我们的初步实验 揭示了肠道微生物MCFA代谢产物（例如5-苯基乙酸）和 Dark GPCR信号（例如GPR84）在AD中使用多词方法和AD患者诱导的多能 干细胞（IPSC）模型。此外，我们确定了靶向肠道微生物代谢物途径的改善 无菌小鼠的认知行为。我们认为将AD患者诱导的IPSC，大脑器官结合在一起， 和无菌小鼠模型，以及血浆和海马肠道微生物的多模式分析 代谢组学数据将使对精确保护机制的机械理解能够提高机械理解 AD/ADRD中的微生物组 - 脑轴。我们的中心统一假设是识别可能的分子 驱动因素（例如，肠道微生物代谢物）和可吸毒的GPCR信号网络 肠脑轴将引起AD的潜在预防和治疗策略。 AIM 1将测试Dark GPR84（a 假定的小胶质细胞基因及其信号传导激活MCFA的微生物组甲状脑轴的基础 通过评估与广告相关的认知和病理学，无菌小鼠中的粪便菌群移植（FMT） 表型和机制。我们将评估差异肠道微生物群落，不靶向和针对性 GPR84 - / - ，5xFAD和CROSS（5xFAD; GPR84 - / - ）中血浆和海马的肠道代谢组学分析 FMT和FMT后的无菌小鼠。 AIM 2将筛选，测试和验证深色GPCR和信号传导 通过肠道微生物群衍生的MCFA代谢产物的网络扰动，使用AD患者衍生的IPSC线 与大脑器官模型的联系。具体而言，我们将评估肠道微生物的物理结合 使用完整的钙通量，Camp Glossenor和β-arrestin Tango的代谢物GPCR相互作用组 测定。 AIM 3将对肠道微生物代谢物生物标志物发现的监督分析和 使用患者等离子体靶向和不靶向的患者血浆对临床相关的AD患者特征的预测建模 肠道微生物代谢组学。总而言之，我们完成无菌小鼠的多学科方法，AD患者 - 衍生的IPSC和大脑器官模型以及人血浆肠道微生物代谢组学将鉴定 潜在的微生物组预防和治疗方法将直接在AD患者中进行测试。