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

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.

项目总结