Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice
前列腺素 E2 的作用和糖尿病小鼠皮肤感染的易感性增强
基本信息
- 批准号:10337275
- 负责人:
- 金额:$ 50.72万
- 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:2020-04-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AbscessAddressAdenosine MonophosphateAntibioticsAntimicrobial ResistanceBiological Response ModifiersCellsChronicClinicalContainmentCyclic AMPDataDiabetes MellitusDiabetic mouseDinoprostoneDiseaseEventExtravasationFDA approvedFailureGenerationsGlucoseHomeostasisHost DefenseHumanHyperglycemiaImmuneImmune responseImmunosuppressionImpairmentIndividualInfectionInfectious Skin DiseasesInflammationInflammation MediatorsInflammatoryInflammatory ResponseIngestionInsulin-Dependent Diabetes MellitusIntegration Host FactorsKnowledgeLesionMisoprostolModelingMolecularMusNecrosisNon-Insulin-Dependent Diabetes MellitusOintmentsOutcomePTPNS1 genePatientsPeriodicityPersonsPhagocytesPredispositionPrevalenceProductionProstaglandinsReporterResolutionRoleScientistSecond Messenger SystemsSecondary toSiteSkinStaphylococcus aureusStructureSystemic infectionTechniquesTestingTissuesTransgenic MiceTransgenic OrganismsTranslatingVulnerable Populationsanalogantimicrobialbaseimprovedin vivoin vivo imaginginhibitorintravital microscopylipid mediatormacrophagemass spectrometric imagingmethicillin resistant Staphylococcus aureusmicrobialmicroscopic imagingmigrationneutrophilnon-diabeticnovel therapeuticspathogenphenomepreventreceptorrepairedresponseskin damagetheoriestissue injurytissue repairwound healing
项目摘要
Summary
Infections caused by Staphylococcus aureus are more frequent and severe in people with both type 1 diabetes
(T1D) and T2D than in healthy individuals. For over a century, it has been suggested that phagocytes from
people with diabetes show poor antimicrobial functions, which created the paradigm that diabetes leads to
immunosuppression. However, hyperglycemia also drives an excessive production of inflammatory mediators
by immune cells. Here, we will take our current knowledge in host defense and diabetes in a different direction.
We speculated that increased susceptibility to infection is due to an uncontrolled localized inflammatory response
that causes skin damage and prevents bacterial elimination. We recently showed that S. aureus skin infection in
diabetic mice was accompanied by unrestrained neutrophil migration to the site of infection, increased the
production of inflammatory mediators, poor abscess formation (a structure that prevents spread to deeper tissues
and systemic infection) and impaired bacterial clearance. We also showed inadequate production of the
pleiotropic lipid mediator prostaglandin E2 (PGE2) in the skin of infected diabetic mice and a topical ointment
containing misoprostol (an FDA-approved PGE analog) restored bacterial clearance during diabetes. Our
preliminary data reveal low PGE2 production could be due to a reduced capacity to phagocytes to ingest and
clear dead cells (efferocytosis), leading to secondary necrosis, leakage of endogenous inflammatory mediators,
tissue injury and poor host defense. We are hypothesizing that deficient efferocytosis during MRSA skin infection
in diabetic mice is responsible for low PGE2 production, which increases inflammation-associated tissue damage
and prevents wound healing to ultimately enhance susceptibility to non-healing skin infections. We will utilize
transgenic mice producing constitutively PGE2 and fluorescent phagocytes, along with state-of-the-art
techniques, including imaging mass spectrometry (IMS), in vivo imaging (IVIS) and intravital microscopy imaging
(IVM) to unveil the role of PGE2 levels, the E prostanoid receptors and downstream effectors in tissue repair
during skin infection in people and mice with diabetes (Aim 1). Next, we are postulating that misoprostol
improves wound healing in the infected skin by increasing the production of actions of the second messenger
cyclic adenosine monophosphate (cAMP) downstream effectors involved in misoprostol-improved host defense
in diabetic mice (Aim 2). In the Aim 3, we will study whether the failure of a repair mechanism involved in the
elimination of dead cells (efferocytosis) leads to deficient PGE2 production and generation of inflammatory
mediators, causing tissue injury in the infected skin of diabetic mice. Our project could rapidly translate into
clinical use to improve the treatment of skin infection in patients with diabetes. With antimicrobial resistance and
increasing prevalence of diabetes worldwide, there is a compelling need for safe, inexpensive, non-antibiotic,
and host-centered approaches to prevent and treat infections.
总结
项目成果
期刊论文数量(0)
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C. Henrique Serezani其他文献
C. Henrique Serezani的其他文献
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{{ truncateString('C. Henrique Serezani', 18)}}的其他基金
Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice
前列腺素 E2 的作用和糖尿病小鼠皮肤感染的易感性增强
- 批准号:
9980677 - 财政年份:2020
- 资助金额:
$ 50.72万 - 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
- 批准号:
8762864 - 财政年份:2014
- 资助金额:
$ 50.72万 - 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
- 批准号:
10005956 - 财政年份:2014
- 资助金额:
$ 50.72万 - 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
- 批准号:
10418725 - 财政年份:2014
- 资助金额:
$ 50.72万 - 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
- 批准号:
9332397 - 财政年份:2014
- 资助金额:
$ 50.72万 - 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
- 批准号:
9088490 - 财政年份:2014
- 资助金额:
$ 50.72万 - 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
- 批准号:
10201714 - 财政年份:2014
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8646977 - 财政年份:2010
- 资助金额:
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Regulation of Toll-like receptor-induced NFkB activation by Gai-coupled receptors
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Regulation of Toll-like receptor-induced NFkB activation by Gai-coupled receptors
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