Strengthening gut barrier integrity with beneficial microbes to increase lifespan and healthspan
利用有益微生物加强肠道屏障完整性,延长寿命和健康寿命
基本信息
- 批准号:10659262
- 负责人:
- 金额:$ 59.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationAddressAdherent CultureAffectAgeAgingAlzheimer&aposs DiseaseAnti-Inflammatory AgentsAttentionBacteriaBacterial AntigensBacterial ToxinsBacteroidesBlood CirculationCardiovascular DiseasesCellsChronic DiseaseCloningCo-ImmunoprecipitationsCognitiveColonColorectal CancerDementiaDeteriorationDietDiffusionDiseaseDrosophila genusEcosystemElderlyEncephalitisExclusionExtravasationFunctional disorderGenesGoalsHealthHomologous GeneHumanIn VitroInflammationInflammatoryIntestinal MucosaIntestinal permeabilityIntestinesKnowledgeLifeLinkLongevityMaintenanceMalignant NeoplasmsMeasuresMemoryMetabolic syndromeMicrobeMusMutateOutcomePenetrationPersonsPhysical FunctionPlayPopulationProcessProteinsRecombinantsRoleTLR4 geneTestingTight JunctionsTranslationsUp-RegulationVertebratesWorkage relatedanti agingbeneficial microorganismcognitive functioncommensal bacteriacomparative genomicsexperimental studyflyfrailtygastrointestinal epitheliumgenetic manipulationgut bacteriagut inflammationgut microbesgut microbiotahealthspanhuman old age (65+)in vivoinnovationintestinal barrierloss of functionmicrobialnovelpreservationpreventsensorsuccess
项目摘要
Many diseases of old age like colorectal cancer and Alzheimer’s disease, as well as the process of aging itself,
have been linked to changes in the composition of microbes in our gut. Moreover, the ability of our gut to exclude
toxic microbial components from our bloodstream (so-called gut barrier function) deteriorates with increasing
age and results in inflammation which, in-turn, can accelerate aging and promote various chronic diseases. Our
long-term goal is to identify bacteria with anti-aging, anti-inflammatory or other beneficial effects on human health
and to understand their mechanism of action. So far, we have discovered that Parabacteroides distasonis (Pd),
a normal gut bacterium, lowers inflammation and strengthens gut barrier function in mice. Furthermore, Pd
increased lifespan and slowed age-relator loss of vigor when fed to fruit flies. The objectives of this application
are to determine whether Pd can extend lifespan and healthspan in mice, understand the importance of a protein
involved in maintaining gut barrier function called ZO-1, and finally to identify the active factor of Pd and its target
molecule. We hypothesize that gut barrier function deteriorates during aging due to loss of ZO-1 expression,
resulting in leakage of bacterial toxins into the bloodstream, inflammation and loss of function. Furthermore,
specific gut bacteria, such as Pd, can be exploited to prevent or slow age-related gut barrier dysfunction, thereby
reducing inflammation and preserving health. The specific aims of the study are to: 1) determine if Pd can
increase lifespan and healthspan in mice; 1a) understand how proteins involved in gut barrier maintenance are
altered by aging and Pd exposure; 2) determine whether altering ZO-1 expression in the colon affects lifespan
and healthspan in mice; 3) identify the active factor of Pd; 3a) identify the mouse target of Pd and 4) determine
the mechanism of fruit fly lifespan extension by Pd. The aims of this study will be addressed by conducting
several inter-related experiments in cells, mice and fruit flies. Firstly, we will compare the lifespan, gut barrier
function, inflammation and various measures of health throughout life, of mice fed diet with or without with added
Pd. Next, we will compare the same readouts between mice with normal, deleted and high ZO-1 expression in
the intestine. Importantly, mice will be subjected to a battery of tests to assess their frailty and cognitive
health – including several measures of memory and brain inflammation that have direct relevance to
Alzheimer’s disease and its Related Dementias (ADRD). To identify the active factor of Pd, we will identify
additional species of bacteria that are able to increase gut barrier function (via ZO-1) and find the genes they
have in common with Pd. These will then be mutated or transferred to other bacteria one by one. Finally, we will
delete the pyd gene, the fly version of ZO-1, and compare the lifespan and age-related loss of vigor to normal
flies in the presence of absence of Pd. Determining whether Pd can extend lifespan and healthspan in mice, as
well as identifying its active factor, will pave the way for this bacterium, or its active factor, to be utilized in
therapies to extend the healthy lifespan and establish ZO-1 as a target for such therapies.
许多老年疾病,如结肠直肠癌和阿尔茨海默病,以及衰老本身的过程,
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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Jimmy W Crott其他文献
Jimmy W Crott的其他文献
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{{ truncateString('Jimmy W Crott', 18)}}的其他基金
Identifying the active factor of an anti-inflammatory chemopreventive bacterium
鉴定抗炎化学预防细菌的活性因子
- 批准号:
10600457 - 财政年份:2021
- 资助金额:
$ 59.24万 - 项目类别:
Strengthening gut barrier integrity with beneficial microbes to increase lifespan and healthspan
利用有益微生物加强肠道屏障完整性,延长寿命和健康寿命
- 批准号:
10616251 - 财政年份:2021
- 资助金额:
$ 59.24万 - 项目类别:
Strengthening gut barrier integrity with beneficial microbes to increase lifespan and healthspan
利用有益微生物加强肠道屏障完整性,延长寿命和健康寿命
- 批准号:
10295986 - 财政年份:2021
- 资助金额:
$ 59.24万 - 项目类别:
Identifying the active factor of an anti-inflammatory chemopreventive bacterium
鉴定抗炎化学预防细菌的活性因子
- 批准号:
10184104 - 财政年份:2021
- 资助金额:
$ 59.24万 - 项目类别:
Effect of paternal B vitamin intake on intestinal tumorigenesis in offspring
父本 B 族维生素摄入量对子代肠道肿瘤发生的影响
- 批准号:
8296488 - 财政年份:2011
- 资助金额:
$ 59.24万 - 项目类别:
Effect of paternal B vitamin intake on intestinal tumorigenesis in offspring
父本 B 族维生素摄入量对子代肠道肿瘤发生的影响
- 批准号:
8202420 - 财政年份:2011
- 资助金额:
$ 59.24万 - 项目类别:
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