Molecular Pathogenesis of enterotoxigenic E. coli associated enteropathy
产肠毒素大肠杆菌相关性肠病的分子发病机制
基本信息
- 批准号:10656056
- 负责人:
- 金额:$ 64.46万
- 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:2023-01-15 至 2027-10-31
- 项目状态:未结题
- 来源:
- 关键词:Acute DiarrheaAddressAdultAffectAgeArchitectureAreaAtrophicAttentionAutomobile DrivingBiogenesisBiological AssayBiologyBrush BorderCessation of lifeCharacteristicsChildCholeraChromatinClinicalCountryCyclic AMPCyclic GMPCyclic NucleotidesDataDehydrationDeveloping CountriesDevelopmentDiagnosisDiarrheaDisadvantagedDiseaseEnteralEnterocytesEpigenetic ProcessEpithelial CellsEpitheliumEscherichia coli InfectionsEssential GenesExposure toFingersFosteringFunctional disorderGene ExpressionGenesGenetic TranscriptionGrowthHealthHyperplasiaImpairmentIn VitroIndividualInfectionIntellectual impairmentIntestinesInvestigationIon ChannelKnowledgeLifeLinkMaintenanceMalnutritionMediatingMolecularMorbidity - disease rateMorphologyNatureNutrientOral Rehydration TherapyPathogenesisPathway interactionsPatientsPhosphorylationPlayPneumoniaProcessProductionProliferatingProtein KinaseResource-limited settingRiskRoleSanitationSecond Messenger SystemsSignal TransductionSiteSmall IntestinesSodium ChlorideSurfaceTestingToxinToxoidsTransposaseTropical sprueVaccinationVaccinesVillusWaterWorkbasebeta catenincell typecellular microvillusdiarrheal diseaseenterotoxigenic Escherichia colihuman capitalin vivoinsightintestinal epitheliumintestinal homeostasisintestinal maturationlow and middle-income countriesmetermortalitymortality riskmouse modelneonatal micenutrient absorptionpathogenpreventprotein activationstem cell differentiationtranscriptomewasting
项目摘要
Project Summary/Abstract
This work focuses on enterotoxigenic Escherichia coli (ETEC), globally the most common bacterial cause of
serious diarrheal illness. Originally identified more than 50 years ago as a cause of severe diarrheal illness in
patients with clinical presentations indistinguishable from cholera, ETEC continue to threaten the lives of many
children in poor regions of the world where sanitation and clean water remain limited. While deaths from
diarrheal illness in low-middle income countries have declined, largely due to deployment of oral rehydration
therapy, the tremendous morbidity associated with these illnesses remains completely unchecked. ETEC are
closely linked to a condition known as environmental enteropathy or environmental enteric dysfunction (EED)
that is complicated by sequelae of malnutrition, stunted growth, and intellectual impairment, robbing poor
countries of badly needed human capital. Children with malnutrition are also at tremendously increased risk of
dying from infectious diarrhea, pneumonia, and other common infections. In addition, ETEC have been linked
to a centuries-old enigmatic disease, known as tropical sprue, that is typically diagnosed in adults with
substantial repeated exposure to these pathogens. With EED it shares features of poor nutrient absorption,
wasting, and alterations of small intestinal morphology.
Much is known about of the molecular pathogenesis of acute diarrheal disease, with heat- labile (LT) and heat-
stable (ST) toxins signaling through cAMP and cGMP second messenger pathways, respectively, to alter
enterocyte ion channels that promote the net efflux of salt and water into the intestinal lumen. However, the
biology underlying enteropathic changes to the small intestine and related sequelae are very poorly
understood. Our recent studies indicate that ETEC toxins compromise cellular messages critical to the
maintenance, biogenesis and function of small intestinal surfaces responsible for nutrient absorption.
The current project will therefore address the following questions:
· “What is the impact of ETEC and its individual toxins on the absorptive architecture of small intestine?”
· “How does repeated ETEC infection affect the overall expression of genes that direct formation of
surfaces needed for nutrient absorption?”
· “Can we mitigate these effects by toxin-neutralizing vaccination?”
Addressing these fundamental questions will fill important gaps in our understanding of the sequelae to ETEC
infections, elucidate important features of the molecular pathogenesis of disease, and inform strategies to
prevent illnesses that threaten millions of disadvantaged children worldwide.
项目总结/摘要
这项工作的重点是产肠毒素大肠杆菌(ETEC),全球最常见的细菌原因,
严重的慢性病。50多年前,
尽管患者的临床表现与霍乱难以区分,但ETEC继续威胁着许多人的生命,
在卫生设施和清洁用水仍然有限的世界贫困地区,虽然死亡人数
中低收入国家的疟疾发病率有所下降,这主要是由于采用了口服补液疗法
尽管如此,与这些疾病相关的巨大发病率仍然完全不受控制。ETEC是
与环境性肠病或环境性肠功能障碍(EED)密切相关
营养不良、发育不良和智力障碍的后遗症使这一问题变得更加复杂,
急需人力资本的国家。营养不良的儿童也面临着极大的风险,
死于感染性腹泻、肺炎和其他常见感染。此外,ETEC还与
一种有着数百年历史的神秘疾病,被称为热带口炎性腹泻,通常在成年人中被诊断为
大量反复接触这些病原体。与EED一样,它具有营养吸收不良的特征,
消耗和小肠形态的改变。
关于急性结肠炎的分子发病机制已经知道很多,其中热不稳定性(LT)和热不稳定性(HT)是急性结肠炎的分子发病机制。
分别通过cAMP和cGMP第二信使途径的稳定(ST)毒素信号传导,以改变
肠上皮细胞离子通道,促进盐和水净流出进入肠腔。但
小肠的肠病性变化和相关后遗症的生物学基础非常差,
明白我们最近的研究表明,ETEC毒素损害细胞信息的关键,
维持、生物发生和负责营养吸收的小肠表面的功能。
因此,本项目将处理以下问题:
·“ETEC及其单个毒素对小肠吸收结构的影响是什么?”
·“反复ETEC感染如何影响指导ETEC形成的基因的整体表达?
吸收养分所需的表面?”
·“我们能否通过毒素中和疫苗来减轻这些影响?”
解决这些基本问题将填补我们对ETEC后遗症理解的重要空白
感染,阐明疾病的分子发病机制的重要特征,并告知战略,
预防威胁全世界数百万弱势儿童的疾病。
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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James Michael Fleckenstein其他文献
James Michael Fleckenstein的其他文献
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{{ truncateString('James Michael Fleckenstein', 18)}}的其他基金
Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections
产肠毒素大肠杆菌感染的分子发病机制
- 批准号:
9884089 - 财政年份:2020
- 资助金额:
$ 64.46万 - 项目类别:
Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections
产肠毒素大肠杆菌感染的分子发病机制
- 批准号:
10438532 - 财政年份:2020
- 资助金额:
$ 64.46万 - 项目类别:
ShEEP Request for ImageXpress Micro Confocal High Content Screening System
ShEEP 请求 ImageXpress Micro 共焦高内涵筛选系统
- 批准号:
10177122 - 财政年份:2020
- 资助金额:
$ 64.46万 - 项目类别:
Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections
产肠毒素大肠杆菌感染的分子发病机制
- 批准号:
10553173 - 财政年份:2020
- 资助金额:
$ 64.46万 - 项目类别:
Molecular Microbiology of Enterotoxigenic E. coli Pathogen-Host Interactions
产肠毒素大肠杆菌病原体-宿主相互作用的分子微生物学
- 批准号:
9926220 - 财政年份:2016
- 资助金额:
$ 64.46万 - 项目类别:
Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections
产肠毒素大肠杆菌感染的分子发病机制
- 批准号:
9275348 - 财政年份:2012
- 资助金额:
$ 64.46万 - 项目类别:
Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections
产肠毒素大肠杆菌感染的分子发病机制
- 批准号:
8965936 - 财政年份:2012
- 资助金额:
$ 64.46万 - 项目类别:
Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections
产肠毒素大肠杆菌感染的分子发病机制
- 批准号:
8245631 - 财政年份:2012
- 资助金额:
$ 64.46万 - 项目类别:
Novel Antigen Identification for an Enterotoxigenic E. coli Vaccine
产肠毒素大肠杆菌疫苗的新抗原鉴定
- 批准号:
8436769 - 财政年份:2010
- 资助金额:
$ 64.46万 - 项目类别:
Novel Antigen Identification for an Enterotoxigenic E. coli Vaccine
产肠毒素大肠杆菌疫苗的新抗原鉴定
- 批准号:
8680121 - 财政年份:2010
- 资助金额:
$ 64.46万 - 项目类别:
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