Development of a microbial-rich exposure regimen to accelerate translational research using mouse models of Alzheimer's Disease to humans.
开发富含微生物的暴露方案,以加速使用阿尔茨海默病小鼠模型对人类的转化研究。
基本信息
- 批准号:10681908
- 负责人:
- 金额:$ 19.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdultAffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease therapyAmyloidAmyloidosisAnimal ModelAnimalsAntigensBasic ScienceBrainBrain StemBrain regionCD8B1 geneCell MaturationCellsCessation of lifeDataDevelopmentDiseaseEnvironmentExposure toFailureFemaleFlow CytometryFutureGeneticGenetic TranscriptionGliosisHippocampusHumanImmuneImmune responseImmune systemImmunohistochemistryImpaired cognitionIncidenceInfiltrationLaboratoriesLiverLymphoidLymphoid TissueMasksMedialMicrobeMicrogliaModelingMolecularMusNeurodegenerative DisordersOrganPathogenesisPathologicPathway interactionsPeripheralPhenotypePlayPopulationPrefrontal CortexPublishingRegimenRegulatory T-LymphocyteReportingReproducibilityResearchResearch PersonnelRodentRoleSenile PlaquesSpleenStainsSynapsesT cell differentiationTauopathiesTestingTissuesTranslatingTranslational ResearchVisualizationWorkamyloid pathologycognitive functioncommensal microbesdefined contributiondesigneffective therapyexperimental studyfightinggerm free conditionhuman diseasehuman modelindexinginsightlymph nodesmalemicrobialmonocytemouse modelneuron lossneuropathologynovelnovel strategiespathogenpathogenic microbepreventresidencetau Proteinstraffickingtraittransmission processtrend
项目摘要
Project Summary
Accumulating evidence over the years suggests that microbial exposure and the ensuing immune response has
a large role in the incidence and progression of age-associated neurodegenerative diseases, including in
Alzheimer’s Disease (AD). Yet, research on this neurodegenerative disease has primarily utilized genetic mouse
models that are reared in ultra-hygienic specific pathogen free (SPF) laboratory environments. The highly
sanitized SPF environment prevents inadvertent microbial exposure and reduces experimental variability. But
without routine microbial stimulation, the immune system of these SPF mice remains in a predominantly naïve
state comprising mostly of antigen-inexperienced immune cell populations. Importantly, these naïve cells remain
sequestered in the lymphoid tissues and do not access disease-affected organs. Thus, studying animals reared
in SPF conditions may mask important contributions of the immune system to neurodegenerative diseases. If
true, this may be a major contributing factor to the failure of translating findings from rodents to humans, which
are naturally exposed to a variety of pathogens. Dr. Beura (co-investigator in this application) has demonstrated
that SPF mice co-housed with pet store mice (herein referred as “dirty” mice) not only have a higher number of
immune cells in peripheral organs, as compared to SPF mice, but their immune cells also display maturation
traits that are more typical of the human immune system. Based on these findings and the known role of the
immune system in AD, we assessed the impact of a pathogen-rich environment on the 5XFAD mouse model of
AD. We present preliminary data demonstrating that the immune system is heightened in dirty compared to SPF
5XFAD mice. Additionally, our preliminary data show increased gliosis in 6-month-old dirty compared to SPF
5XFAD mice. While these findings are promising, cohousing approaches have several shortcomings that limit its
wider deployment, including variable transmission of pathogens and fighting among male mice. To overcome
these limitations, we developed a new microbial exposure regimen that optimizes pathogen transmission leading
to reproducible changes in the immune system of both male and female mice. In this proposal, we will use this
novel regimen to define the contribution of a pathogen-rich environment and matured plus heightened immune
system on AD mouse models of amyloid pathology. To establish this novel approach, we will perform
experiments in two aims. First, we will determine the impact of a pathogen-rich environment on immune
maturation in two mouse models of AD amyloid neuropathology, 5XFAD and APPNL-F, and a mouse model of AD
tauopathy, PS19. Second, we will determine the timing and magnitude of AD pathological indices in 5XFAD,
APPNL-F and PS19 mice exposed to dirty and SPF conditions. Together, the proposed experiments will provide
unique insights about the underpinning of AD pathogenesis and reveal unique contributions of a microbe-rich
environment and matured immune system.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gregorio Valdez其他文献
Gregorio Valdez的其他文献
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{{ truncateString('Gregorio Valdez', 18)}}的其他基金
Role of synaptic Schwann cells in NMJ and skeletal muscle aging
突触雪旺细胞在 NMJ 和骨骼肌衰老中的作用
- 批准号:
10688321 - 财政年份:2022
- 资助金额:
$ 19.94万 - 项目类别:
Targeting the fibroblast growth factor binding protein-1 to slow degeneration of neuromuscular junctions
靶向成纤维细胞生长因子结合蛋白-1 减缓神经肌肉接头的退化
- 批准号:
9290385 - 财政年份:2017
- 资助金额:
$ 19.94万 - 项目类别:
Targeting the fibroblast growth factor binding protein-1 to slow degeneration of neuromuscular junctions
靶向成纤维细胞生长因子结合蛋白-1 减缓神经肌肉接头的退化
- 批准号:
9903183 - 财政年份:2017
- 资助金额:
$ 19.94万 - 项目类别:
Dysregulated cholinergic transmission contributes to aging of the lower motor system
胆碱能传输失调导致下运动系统老化
- 批准号:
9565885 - 财政年份:2017
- 资助金额:
$ 19.94万 - 项目类别:
Synaptic FGFs are required and sufficient to maintain and repair aged NMJs
突触 FGF 是维持和修复老化 NMJ 所必需的且足够的
- 批准号:
9143829 - 财政年份:2015
- 资助金额:
$ 19.94万 - 项目类别:
Role of Target-derived FGFs in Maintaining and Repairing Synapses
靶标衍生的 FGF 在维持和修复突触中的作用
- 批准号:
8618387 - 财政年份:2013
- 资助金额:
$ 19.94万 - 项目类别:
Role of Target-derived FGFs in Maintaining and Repairing Synapses
靶标衍生的 FGF 在维持和修复突触中的作用
- 批准号:
8738734 - 财政年份:2013
- 资助金额:
$ 19.94万 - 项目类别:
Role of Target-derived FGFs in Maintaining and Repairing Synapses
靶标衍生的 FGF 在维持和修复突触中的作用
- 批准号:
8896083 - 财政年份:2013
- 资助金额:
$ 19.94万 - 项目类别:
Molecular basis of age-related synaptic alterations
年龄相关突触改变的分子基础
- 批准号:
7539575 - 财政年份:2008
- 资助金额:
$ 19.94万 - 项目类别:
Molecular basis of age-related synaptic alterations
年龄相关突触改变的分子基础
- 批准号:
7683976 - 财政年份:2008
- 资助金额:
$ 19.94万 - 项目类别:
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