Pathobiology of MRSA-induced Endothelial Permeability and Acute Lung Injury
MRSA 诱导的内皮通透性和急性肺损伤的病理学
基本信息
- 批准号:10608606
- 负责人:
- 金额:$ 65.27万
- 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:2022-12-20 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:Acute Lung InjuryAcute Respiratory Distress SyndromeAddressAgonistAntibiotic ResistanceAttenuatedBacteriaBlood flowCYP1A1 geneChIP-seqCritical IllnessDataDevelopmentDiseaseEndothelial CellsEndotheliumEnzymesEpigenetic ProcessFunctional disorderGene ExpressionGenesGram-Positive BacteriaHealthHistone AcetylationHistone DeacetylaseHumanImmune responseIn VitroInflammationInflammatoryInflammatory ResponseInjuryInterventionKnowledgeLifeLungMedicalModelingMolecularMorbidity - disease rateMusOrganismPathogenicityPatientsPermeabilityPharmacologic SubstancePhospholipidsPlayPneumoniaPre-Clinical ModelProcessPropertyReportingResistanceRoleSepsisSignal TransductionSourceStaphylococcus aureusStaphylococcus aureus infectionTargeted ResearchTestingTherapeuticUbiquitinationVascular Endothelial CellVirulentWorkanalogclinically relevantefficacy evaluationimprovedin vivoinflammatory lung diseaseinsightlung injurymethicillin resistant Staphylococcus aureusmortalitynew therapeutic targetnovelnovel therapeuticsorgan injurypharmacologicphosphonateprotective pathwayreceptorresistant strainresponsescreeningsepsis induced ARDSsphingosine 1-phosphatetargeted treatmenttherapeutic candidatetherapeutic effectivenesstherapy developmenttooltrafficking
项目摘要
SUMMARY:
Despite decades of targeted research, no effective pharmacologic interventions have been identified for the
Acute Respiratory Distress Syndrome (ARDS), which is a life-threatening disease process characterized by
dysregulated immune responses. Sepsis is a major cause of ARDS, and the pathophysiology of both
processes is characterized by alterations in microcirculatory blood flow, with vascular endothelial cell (EC)
dysfunction playing a major role in organ injury. Novel mechanistic insights are needed to assist the
development of therapies to address the EC barrier dysfunction that underlies ARDS and sepsis.
Staphylococcus (S.) aureus is a frequently identified organism in gram-positive sepsis, and the highly virulent,
antibiotic-resistant methicillin-resistant S. aureus (MRSA) strain is particularly challenging to treat and a major
cause of ARDS. Important knowledge gaps exist both in MRSA-induced pathophysiology relevant to ARDS
and in the mechanistic understanding of EC-specific processes that can be targeted therapeutically.
Endogenous sphingosine-1-phosphate (S1P) and the structurally similar pharmaceutical compound, FTY720
(FTY), have EC barrier-enhancing effects in preclinical models of ARDS. However, both S1P and FTY also
induce a myriad of other effects that are potentially harmful in critically ill patients and make them poor
therapeutic candidates. We therefore have explored the barrier-regulatory properties of novel FTY720 analogs
to better understand how these compounds regulate permeability. Our work has revealed that FTY720 (S)-
phosphonate (Tys) has superior efficacy in several preclinical models and maintains expression levels of the
essential S1PR1 receptor, unlike other agonists which induce its degradation. In addition, epigenetic processes
are increasingly being recognized as important pathogenic steps during inflammatory acute lung injury
(ALI)/ARDS and sepsis, and epigenetic responses (such as histone acetylation) can be altered by S1P-related
signaling. Our central hypothesis is that MRSA causes EC dysfunction relevant to ARDS by epigenetic and
other pathophysiologic mechanisms that can be targeted by Tys/S1PR1-related signaling. Using ChIP-seq
analysis and other epigenetic tools, we have generated new insights that MRSA triggers histone acetylation in
lung EC to regulate genes involved in lung EC dysfunction. Exciting new data suggest Tys-S1PR1 signaling
may ameliorate key aspects of these epigenetic effects. Aim #1 will determine the mechanisms by which
Tys/S1PR1 signaling protects against MRSA-induced lung EC barrier disruption in vitro. Aim #2 will use state-
of-the-art ChIP-seq and other approaches to characterize novel MRSA- and Tys/S1PR1-induced epigenetic
changes that have functional consequences in lung EC, including the novel MRSA target identified by our
epigenetic screening, CYP1A1. Aim #3 will extend these studies in vivo by characterizing epigenetic and other
mechanisms of MRSA-induced lung injury in mice and determine the efficacy of Tys. Overall, these studies will
advance our mechanistic understanding of MRSA-induced ARDS to identify novel therapeutic targets.
简介:
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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STEVEN M DUDEK其他文献
STEVEN M DUDEK的其他文献
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{{ truncateString('STEVEN M DUDEK', 18)}}的其他基金
Fostering Academic Physician-Investigators Treating High Risk Populations
培养治疗高危人群的学术医师研究人员
- 批准号:
10647841 - 财政年份:2021
- 资助金额:
$ 65.27万 - 项目类别:
Fostering Academic Physician-Investigators Treating High Risk Populations
培养治疗高危人群的学术医师研究人员
- 批准号:
10459247 - 财政年份:2021
- 资助金额:
$ 65.27万 - 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
- 批准号:
10472480 - 财政年份:2019
- 资助金额:
$ 65.27万 - 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
- 批准号:
10700843 - 财政年份:2019
- 资助金额:
$ 65.27万 - 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
- 批准号:
9791769 - 财政年份:2019
- 资助金额:
$ 65.27万 - 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
- 批准号:
10198029 - 财政年份:2019
- 资助金额:
$ 65.27万 - 项目类别:
Crosstalk between S1P Receptor 1/S1P1 and P-Selectin/Selp in Regulation of Inflammatory Vascular Permeability
S1P 受体 1/S1P1 和 P-选择素/Selp 之间的串扰调节炎症血管通透性
- 批准号:
10871784 - 财政年份:2016
- 资助金额:
$ 65.27万 - 项目类别:
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