Mechanistic role of membrane pore formation in lung-endothelial barrier failure due to blood-borne pathogens.
Mechanistic role of membrane pore formation in lung-endothelial barrier failure due to blood-borne pathogens.
批准号:
10513061
负责人:
Jahar Bhattacharya
金额:
$75.09万
依托单位国家:
美国
项目类别:
财政年份:
1985
资助国家:
美国
项目状态:
未结题
起止时间:
1985-06-01 至 2026-07-31
关键词:
ActinsAcute Lung InjuryAcute Respiratory Distress SyndromeAddressAlveolarBacteremiaBacteriaBiologicalBloodBlood-Borne PathogensCASP1 geneCalcineurinCaspaseCell membraneCellsConfocal MicroscopyCytosolDimensionsDiseaseDoseEndothelial CellsEndotheliumEnhancersEventF-ActinFailureFlagellaGap JunctionsGoalsInflammasomeInhalationInjectionsIntravenousKnowledgeLungLung infectionsMembraneModelingMolecularMusN-terminalPathogenesisPathologyPeritonitisPermeabilityPhaseProcessProteinsPseudomonas aeruginosaPseudomonas aeruginosa infectionPulmonary InflammationResearchRoleSepsisSeveritiesSystemSystemic infectionTailTextTherapeuticTimeTransfectionVeinsacronymseffective therapygenetic manipulationintraperitoneallung injurymortalityneutrophilnovelopportunistic pathogenrepairedresponsesepsis induced ARDSsepticsex
中文摘要
项目概要
意义。总体目标是确定急性呼吸窘迫的机制和治疗方法
机会性病原体铜绿假单胞菌 (PA) 引起的败血性菌血症 (ARDS)。
这些机制仍未定义。我们的前提是血源性 PA 会迅速导致 ARDS
内化于肺内皮。因此,gasdermin D 机制被激活
膜孔的形成。 Ca2 通过孔进入内皮细胞质,破坏 f-肌动蛋白的稳定性,
从而诱发屏障失效——ARDS的主要原因。
方法。我们将通过实时共焦显微镜评估两个具体目标的前提
(RCM)活体小鼠肺,以及其他一般方法。在 SA1 中,我们将确定 LPS 的影响
肺内皮细胞转染,PA 相关 LPS 内化模型。在 SA2 中,我们将确定
通过静脉注射 PA 模拟菌血症的肺内皮效应,以及通过静脉注射 PA 模拟的肺外脓毒症
腹腔内PA感染。前提将在基因操纵小鼠中进行评估,以评估(i)
Gasdermin D 和膜孔形成的其他假说; (ii) ESRT 的毛孔修复机制-
三系统; (iii) 孔诱导的 Ca2 和 f-肌动蛋白机制在屏障失效中的作用; (iv) PA 的影响
肺内皮的内化; (v) 细胞增强内皮肌动蛋白的功效
通透性蛋白可有效治疗 PA 腹膜炎引起的 ARDS。
影响。我们的研究将首次揭示肺内皮孔形成作为一种机制的重要性。
内皮屏障衰竭的机制是脓毒症引起的肺外ARDS的基础
PA 感染。 PA 的内皮内化将被理解为这一过程中的关键机制。
病理学。将首次揭示内皮孔形成的动力学和机制。
针对内皮孔形成(因此屏障失效)的分子策略将被评估为
治疗 PA 脓毒症引起的 ARDS。将在机制和方面取得非常新颖的理解
由于 PA 诱导的孔形成而导致脓毒症引起的 ARDS 的治疗。
英文摘要
PROJECT SUMMARY
Significance. The overall goals are to define mechanisms and therapies for the acute respiratory distress
syndrome (ARDS) due to septic bacteremia of the opportunistic pathogen, Pseudomonas aeruginosa (PA).
These mechanisms remain undefined. Our premise is that blood-borne PA cause ARDS by rapidly
internalizing in the lung endothelium. Consequently, there is activation of the gasdermin D mechanism of
membrane pore formation. Ca2+ enters the endothelial cytosol through the pores, destabilizing f-actin, and
thereby inducing barrier failure – the major cause of ARDS.
Approach. We will evaluate the premise in two Specific Aims by means of real-time confocal microscopy
(RCM) of live mouse lungs, as well as other general approaches. In SA1, we will determine the effects of LPS
transfection of the lung endothelium, a model of PA-associated LPS internalization. In SA2, we will determine
lung-endothelial effects of bacteremia, modeled by intravenous PA injection, and extra-pulmonary sepsis by
intraperitoneal PA infection. The premise will be evaluated in genetically manipulated mice to evaluate (i) the
gasdermin D and other hypotheses of membrane pore formation; (ii) mechanisms of pore repair by the ESCRT-
III system; (iii) the role of pore-induced Ca2+ and f-actin mechanisms in barrier failure; (iv) effects of PA
internalization in the lung endothelium; and (v) the efficacy of endothelial actin enhancement by cell-
permeable proteins as effective therapy against ARDS due to PA peritonitis induced.
Impact. Our studies will for the first time, reveal the importance of lung-endothelial pore formation as a
mechanism of the endothelial barrier failure that underlies sepsis-induced ARDS due to extra-pulmonary
infection by PA. The endothelial internalization of PA will be understood as the critical mechanism in this
pathology. The dynamics and mechanisms of endothelial pore formation will be revealed for the first time.
Molecular strategies directed against endothelial pore formation, therefore barrier failure, will be evaluated as
therapies for ARDS due to PA sepsis. Outstandingly novel understanding will be achieved in mechanisms and
therapies of sepsis-induced ARDS due to PA-induced pore formation.
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会议论文
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