Distal gut microbiome targets of host anti-proteolytic proteins during colitis
结肠炎期间宿主抗蛋白水解蛋白的远端肠道微生物组目标
基本信息
- 批准号:10320030
- 负责人:
- 金额:$ 22.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-12-18 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:AbateAddressAffinityAlgorithmsAnimal ModelAnti-Bacterial AgentsAnti-Inflammatory AgentsAntiinflammatory EffectBindingBinding ProteinsBioinformaticsBiologicalBiologyC57BL/6 MouseCellsChemicalsChronicColitisCollaborationsCollectionColorectal CancerCommunitiesControl GroupsCysteineDataDevelopmentDiseaseDistalDrug TargetingElastasesEnzymesExperimental DesignsFamilyFemaleFutureGeneticGenomicsGoalsHandHarvestHomeostasisHumanIleitisImmuneImmunocompromised HostIn VitroInfiltrationInflammationInflammatoryInjectionsIntestinal ContentIntestinal MucosaIntestinesKnowledgeLaboratoriesLettersLibrariesLiquid ChromatographyMapsMass Spectrum AnalysisMeasuresMetabolismMethodologyMethodsModelingMusObesityPI3 geneParentsPatientsPeptide HydrolasesPropertyProteinsProteomeProteomicsPublishingRag1 MouseResearchRoleSamplingSerineSerine ProteaseT cell therapyT-LymphocyteTechnologyTimeTranslationsTrypsinantimicrobialbasebiochemical modelchemically induced colitiscommensal bacteriadrug discoverygut inflammationgut microbiomein vivointerestmetaproteomicsmicrobialmicrobial hostmicrobiomemouse modelmurine colitispathogenic bacteriaresponsesmall moleculestemtandem mass spectrometrytherapeutic target
项目摘要
Title: Distal gut microbiome targets of host anti-proteolytic proteins during colitis
ABSTRACT
Our long-term goal is to advance our understanding of the distal gut microbiome from its basis in genomics
with chemical biology and quantitative metaproteomics approaches. Over the last several years, we have
developed a combination of chemical probe-based technologies, liquid chromatography tandem mass
spectrometry (LC-MS/MS) proteomics, and bioinformatic analyses as approaches to interrogate and quantitate
specific enzyme families in microbiome proteomes. We recently showed that colitic mice have a dramatic
elevation in microbiome-secreted proteases within the distal gut relative to healthy mice using these combined
methods. Correspondingly, we observe a significant increase in host anti-proteolytic proteins (APPs).
Gut inflammation can be abated in colitis mouse models upon introduction of human APPs a-1-antitrypsin or
elafin. While we posit that a-1-antitrypsin and elafin (and other APPs) reduce inflammation via inhibition of
aberrant proteolytic activities, both APPs also have antimicrobial activity. Thus, the anti-inflammatory mechanism
by which antitrypsin and elafin act could be primarily, or in part, attributable to altering bacterial composition.
Our primary question is if APPs target microbial proteases. Here, we will elucidate the microbiome (and host)
protein targets of six APPs overproduced in response to distal gut inflammation. These six APPs collectively
target proteases from the serine, cysteine, and metallo subfamilies. We have purified all APPs of interest and
aim to employ the proteins as “bait” to determine if these APPs primarily target the inhibition of bacterial
proteases. We will subsequently identify and quantitate the APP-captured proteins with our LC-MS/MS
metaproteomics methods. We propose to focus our APP-enrichment strategy and metaproteomics on a well-
established adoptive T cell transfer murine model of chronic colitis and directly compare to control mice raised
under identical conditions. Our preliminary data confirms that a-1-antitrypsin irreversibly binds a unique collection
of secreted proteins within colitic microbiome samples compared to controls. This is significant, as expression
levels of host elastase and trypsin (targets of a-1-antitrypsin) are similar between the colitis and control groups.
Over the next two years, we anticipate that we will identify several families of host APP-targeted bacterial
proteases upregulated in colitic mice, as classified by sequence and/or structural homology. This list of proteases
will help guide and focus future biochemical, cell-based, and animal model research on specific protease families
as potential inflammatory agents (and therapeutic targets), as well as provide an optimized APP-enrichment
methodology for translation into human IBD patients and other microbiome-related diseases.
题目:结肠炎期间宿主抗蛋白水解蛋白的远端肠道微生物靶点
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Howard C Hang其他文献
Howard C Hang的其他文献
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{{ truncateString('Howard C Hang', 18)}}的其他基金
Microbiota, Probiotic and Dietary Metabolite Control of Enteric Pathogen Virulence
微生物群、益生菌和膳食代谢物对肠道病原体毒力的控制
- 批准号:
10562497 - 财政年份:2022
- 资助金额:
$ 22.19万 - 项目类别:
Translation of commensal bacteria mechanism for immunotherapy
共生菌免疫治疗机制的转化
- 批准号:
10311095 - 财政年份:2019
- 资助金额:
$ 22.19万 - 项目类别:
Translation of commensal bacteria mechanism for immunotherapy
共生菌免疫治疗机制的转化
- 批准号:
10533309 - 财政年份:2019
- 资助金额:
$ 22.19万 - 项目类别:
Translation of commensal bacteria mechanism for immunotherapy
共生菌免疫治疗机制的转化
- 批准号:
10064132 - 财政年份:2019
- 资助金额:
$ 22.19万 - 项目类别:
Translation of commensal bacteria mechanism for immunotherapy
共生菌免疫治疗机制的转化
- 批准号:
10379772 - 财政年份:2019
- 资助金额:
$ 22.19万 - 项目类别:
Elucidation of Commensal Bacteria Mechanisms Required for Host Protection
阐明宿主保护所需的共生细菌机制
- 批准号:
9894505 - 财政年份:2013
- 资助金额:
$ 22.19万 - 项目类别:
Elucidation of Commensal Bacteria Mechanisms Required for Host Protection
阐明宿主保护所需的共生细菌机制
- 批准号:
8594254 - 财政年份:2013
- 资助金额:
$ 22.19万 - 项目类别:
Elucidation of Commensal Bacteria Mechanisms Required for Host Protection
阐明宿主保护所需的共生细菌机制
- 批准号:
8412902 - 财政年份:2013
- 资助金额:
$ 22.19万 - 项目类别:
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