The Role of Bile Salt Hydrolase in Glucose Metabolism
胆盐水解酶在葡萄糖代谢中的作用
基本信息
- 批准号:10365160
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAgonistBackBacteriaBile AcidsBlindnessBlood GlucoseCholesterol HomeostasisDataDiabetes MellitusDiabetic mouseDietDietary FatsDietary intakeDiseaseEcologyEnergy MetabolismEngineeringEnvironmentEnzymesEscherichia coliGeneral PopulationGenesGluconeogenesisGlucoseGoalsHealthHepaticHigh Fat DietHomeostasisHormonesHydrolaseImmune responseInsulinIntakeKidney FailureKnock-inKnockout MiceLinkLower ExtremityMediatingMetabolicMetabolic BiotransformationMetabolic syndromeMetabolismMetagenomicsMissionModelingModificationMorbidity - disease rateMusNon-Insulin-Dependent Diabetes MellitusNutrientObese MiceOutcomeOutcome StudyPerformancePhysiologicalPhysiologyPlayPopulationPrevalenceProductionResearchResearch PersonnelRibosomal RNARoleSerumSignal PathwaySignal TransductionSourceTestingTranscriptUnited States Department of Veterans AffairsVeteransWild Type Mouseabsorptionantagonistbile saltsblood glucose regulationdiet-induced obesityglucose metabolismglucose toleranceglycogenesisgut microbiomegut microbiotahepatic gluconeogenesisimprovedinnovationinsulin sensitivityinterestlimb amputationmetabolic abnormality assessmentmicrobialmicrobiomemicrobiome researchmicroorganismmortalitymuricholic acidnew therapeutic targetnovel strategiesreceptorresearch and developmentresponsetooltranscriptome sequencingtranslational impactvector
项目摘要
PROJECT SUMMARY/ABSTRACT
Currently, 34.2 million US adults, or approximately 10.3% of the total population, have diabetes. The
prevalence of diabetes is two-fold higher among Veterans (20.5%) and it is the leading cause of kidney failure,
lower-limb amputations, and adult-onset blindness both in Veterans and the general population. Over the last
two decades, multiple metabolic studies have demonstrated that bile acids play an unexpected but important
role in glucose homeostasis and metabolic syndrome. Correlational 16S and metagenomic studies suggest that
gut microflora can affect host glucose homeostasis through modification of bile acids. The overall goal of this
proposal is to determine the mechanisms by which the gut microflora affect host glucose homeostasis. To have
a better functional understanding of this relationship, investigators need to assess the role of specific bacterial
bile acid biotransformations and investigate their effects on the gut luminal ecology, the flux of metabolites and
nutrients, and ultimately, physiology in conventionally-raised (as opposed to microbiome-depleted) hosts. Thus,
there is a critical need for a tool that will facilitate knocking-in of specific bacterial functions into the gut
microbiome and investigate their effects on the host glucose metabolism and insulin sensitivity.
The investigators demonstrate an innovative strategy that addresses this need using engineered native
bacteria. This novel approach allows quick and effective knocking-in of a beneficial function into the gut
microbiome. The function is sustained, potentially for perpetuity, in conventionally-raised hosts with a single
treatment and without the need for microbiome depletion. To date, the investigators have demonstrated that
tractable native bacteria can be engineered to modify bile acids ex vivo, reintroduced to the host, engraft the
entire gut, deliver an intended beneficial function, alter luminal and serum metabolites as intended, affect host
metabolism, and even reverse disease. These functions affect host physiology and potentially alleviate disease.
Using this new approach, the investigators will pursue the overall goal by addressing the central hypothesis that
gut microbiome affects host insulin sensitivity through bile acid deconjugation and that these functions can be
used to treat type 2 diabetes.
In the next four years, the investigators will pursue the proposal's central hypothesis with three specific aims.
The first aim will determine if bacterial bile acid deconjugation affects ileal and hepatic glucoregulatory transcripts
in conventionally-raised C57Bl6 mice. Ultimately this aim will determine the relationship between bacterial bile
acid modification and host bile acid signaling, gluconeogenesis, and incretin production. The second aim will
determine if the glucoregulatory effects of microbial bile acid deconjugation are mediated by the farnesoid X
receptor (FXR), a major bile acid receptor. This will be done using engineered native bacteria with and without
BSH in FXR knockout mice. In the end, this aim will determine the importance of the role of FXR in mediating
the metabolic effects of gut microbiome. The third aim will determine how diet affects the bacterial bile acid
deconjugation influence on the host metabolic homeostasis, using both the diet-induced obesity model (which
uses a high-fat diet) and ob/ob mice (which uses normal chow diet). Because bile acid signaling is heavily
influenced by diet, this aim will further elucidate the relationship between bacterial bile acid modifications, nutrient
intake, and host glucoregulatory response.
The expected outcome of these studies is a better understanding of a) how the gut microbiome affects host
glucose regulation and b) whether the gut microbiome can be manipulated to improve insulin sensitivity. The
outcome will have a positive translational impact because it will lead to novel therapeutic targets to T2D using
the signaling pathways and functions employed by the gut microbiome.
项目总结/文摘
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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Amir Zarrinpar其他文献
Amir Zarrinpar的其他文献
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{{ truncateString('Amir Zarrinpar', 18)}}的其他基金
Bacterial DNA as a Diagnostic Biomarker of Hepatocellular Carcinoma
细菌 DNA 作为肝细胞癌的诊断生物标志物
- 批准号:
10557105 - 财政年份:2022
- 资助金额:
-- - 项目类别:
The Role of Bile Salt Hydrolase in Glucose Metabolism
胆盐水解酶在葡萄糖代谢中的作用
- 批准号:
10617180 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Bacterial DNA as a Diagnostic Biomarker of Hepatocellular Carcinoma
细菌 DNA 作为肝细胞癌的诊断生物标志物
- 批准号:
10357369 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Engineering Native E. coli to Detect, Report, and Treat Colorectal Cancer
改造天然大肠杆菌来检测、报告和治疗结直肠癌
- 批准号:
10330342 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Engineering Native E. coli to Detect, Report, and Treat Colorectal Cancer
改造天然大肠杆菌来检测、报告和治疗结直肠癌
- 批准号:
10700076 - 财政年份:2021
- 资助金额:
-- - 项目类别:
The Role of Altered Luminal Dynamics in OSA-Induced Atherosclerosis
管腔动力学改变在 OSA 诱发的动脉粥样硬化中的作用
- 批准号:
10273745 - 财政年份:2021
- 资助金额:
-- - 项目类别:
The Role of Altered Luminal Dynamics in OSA-Induced Atherosclerosis
管腔动力学改变在 OSA 诱发的动脉粥样硬化中的作用
- 批准号:
10455260 - 财政年份:2019
- 资助金额:
-- - 项目类别:
The Role of Altered Luminal Dynamics in OSA-Induced Atherosclerosis
管腔动力学改变在 OSA 诱发的动脉粥样硬化中的作用
- 批准号:
10217244 - 财政年份:2019
- 资助金额:
-- - 项目类别:
The Role of Altered Luminal Dynamics in OSA-Induced Atherosclerosis
管腔动力学改变在 OSA 诱发的动脉粥样硬化中的作用
- 批准号:
10884617 - 财政年份:2019
- 资助金额:
-- - 项目类别:
The Role of Altered Luminal Dynamics in OSA-Induced Atherosclerosis
管腔动力学改变在 OSA 诱发的动脉粥样硬化中的作用
- 批准号:
10456644 - 财政年份:2019
- 资助金额:
-- - 项目类别:
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