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.
总结:
尽管进行了数十年的靶向研究,但尚未确定有效的药物干预措施。
急性呼吸窘迫综合征(ARDS),是一种危及生命的疾病过程,其特征在于:
免疫反应失调脓毒症是ARDS的主要原因,
过程的特征在于微循环血流的改变,血管内皮细胞(EC)
在器官损伤中起主要作用的功能障碍。需要新的机械见解来帮助
开发治疗以解决作为ARDS和脓毒症基础的EC屏障功能障碍。
葡萄球菌(S.)金黄色葡萄球菌是革兰氏阳性脓毒症中经常鉴定的生物体,并且高毒性,
耐甲氧西林S.金黄色葡萄球菌(MRSA)菌株的治疗特别具有挑战性,
因为ARDS。在MRSA诱导的与ARDS相关的病理生理学方面,
以及对EC特异性过程的机制理解,这些过程可以在治疗上靶向。
内源性鞘氨醇-1-磷酸(S1 P)和结构相似的药物化合物FTY 720
(FTY),在ARDS的临床前模型中具有EC屏障增强作用。然而,S1 P和FTY也
会引起无数其他对危重病人有潜在危害的影响,使他们变得贫穷
治疗候选人。因此,我们探索了新型FTY 720类似物的屏障调节特性
以更好地了解这些化合物如何调节渗透性。我们的工作表明,FTY 720(S)-
膦酸盐(Tys)在几种临床前模型中具有上级功效,并维持
必需的S1 PR 1受体,不像其他激动剂诱导其降解。此外,表观遗传过程
越来越多地被认为是炎症性急性肺损伤的重要致病步骤
(ALI)/ARDS和脓毒症,以及表观遗传反应(如组蛋白乙酰化)可以被S1 P相关的
发信号。我们的中心假设是MRSA通过表观遗传学和免疫学途径引起与ARDS相关的EC功能障碍,
Tys/S1 PR 1相关信号传导可靶向的其他病理生理机制。使用ChIP-seq
分析和其他表观遗传工具,我们已经产生了新的见解,MRSA触发组蛋白乙酰化,
肺EC调节参与肺EC功能障碍的基因。令人兴奋的新数据表明Tys-S1 PR 1信号传导
可能会改善这些表观遗传效应的关键方面。目标#1将确定
Tys/S1 PR 1信号通路在体外保护免于MRSA诱导的肺EC屏障破坏。目标#2将使用状态-
最先进的ChIP-seq和其他方法来表征新型MRSA和Tys/S1 PR 1诱导的表观遗传
在肺EC中具有功能性后果的变化,包括我们发现的新型MRSA靶点。
表观遗传学筛查,CYP 1A 1。目标#3将通过表征表观遗传和其他遗传学特征来扩展这些体内研究。
在小鼠中研究MRSA诱导的肺损伤的机制,并确定Tys.总的来说,这些研究将
推进我们对MRSA诱导的ARDS机制的理解,以确定新的治疗靶点。
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)
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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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