Role of heme and PGP matrikines in lung inflammation
血红素和 PGP 基质素在肺部炎症中的作用
基本信息
- 批准号:10468254
- 负责人:
- 金额:$ 54.72万
- 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:2020-09-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Lung InjuryAddressAttenuatedBindingBiochemicalBiological AssayBlood CirculationC57BL/6 MouseCause of DeathClinicalCollagenCritical IllnessDataDependenceDiseaseEndotheliumEpithelialEpithelial CellsExposure toExtracellular MatrixFemaleFunctional disorderGenerationsGlycineGoalsHemeHemopexinHumanIL8RB geneIn VitroIndividualInflammationInflammation MediatorsInflammatoryLinkLiquid substanceLungMass Spectrum AnalysisMeasuresMediatingMediator of activation proteinModelingMolecularMorbidity - disease rateMusOrganOutcomePathogenesisPathway interactionsPatientsPeptide HydrolasesPeptidesPermeabilityPharmacologyPhase II Clinical TrialsPlasmaProlineProtease InhibitorProteinsPublic HealthPulmonary InflammationReactive Oxygen SpeciesRoleSamplingSecondary toSepsisSeptic ShockSeverity of illnessSignal TransductionSignaling ProteinTestingTherapeuticairway epitheliumcadherin 5cecal ligation punctureendopeptidase Aexosomeextracellularheme ahuman modelimprovedin vivoin vivo evaluationinhibitorinsightlung developmentlung injurylung microvascular endothelial cellsmalemonolayermortalitymouse modelnew therapeutic targetnovelpredict clinical outcomepreventprolinalprolyl oligopeptidaseprolyl-glycyl-prolineprolyl-prolinesepsis induced acute lung injuryseptic patientssmall moleculetherapeutic target
项目摘要
PROJECT SUMMARY:
Sepsis-related acute lung injury (ALI), characterized by increased lung permeability and inflammation remains a
significant cause of death in critically ill individuals. Several inflammatory mediators and mechanisms underlying
increased lung leak have been identified, which while leading to improved therapeutics, have plateaued
suggesting as yet undefined mechanisms, and / or interactions between distinct mediators. In this proposal, we
build upon our preliminary data showing that proline-glycine-proline (PGP) peptides derived from the matrix
protein collagen, are increased in human and murine models of sepsis, and that these matrikines promote lung
leak via CXCR2 activation. In this application, we address the following three questions i) What mechanisms
regulate PGP formation? We hypothesize that free heme, a newly identified mediator of sepsis pathogenesis,
stimulates the release of exosomes containing active prolyl endopeptidase (PE), a protease that catalyzes the
terminal step of collagen breakdown to PGP in the extracellular compartment. Preliminary data show scavenging
of heme by hemopexin decreases circulating PGP levels in vivo; ii) Does endogenous PGP mediate sepsis
induced lung permeability? Preliminary data show that administration of Arg-Thr-Arg (RTR), a peptide that
selectively binds and inhibits PGP, prevents lung leak in vitro and vivo; iii) Does PGP associate with severity of
disease and ALI in human sepsis? Preliminary data show increases in circulating PGP peptides in human sepsis
and demonstrate that this is able to elicit pro-permeability signaling. We propose 3 aims to test our hypothesis
that PGP matrikines mediate sepsis-ALI, SA1: Determine the role and mechanisms by which free heme
mediates PGP peptide formation. SA2: Determine the role and mechanisms by which PGP mediates sepsis-ALI
and SA3: Determine whether plasma levels of free heme, PE-exosomes, and PGP peptides correlate both
clinical outcomes and development of lung injury in patients with sepsis. We propose to use a combination of
primary human epithelial cells, pulmonary microvascular endothelial cells and the cecal-ligation puncture model
of sepsis using C57Bl/6 male and female mice to test our hypothesis, and couple this with biochemical and
molecular approaches to measure protease activity, free heme levels, exosomes and PGP peptide levels.
Mechanistic insights will be gained using selective inhibitors of heme, PGP and proteases that generate PGP,
as well as a novel endothelial targeted CXCR2-/- mouse model generated for the proposed studies. Successful
completion of these aims will significantly improve our understanding of mechanisms underlying sepsis-ALI with
a specific emphasis on protease containing exosomes and matrikines as new mediators and therapeutic targets
in this debilitating disorder.
项目概要:
脓毒症相关的急性肺损伤(ALI),其特征是肺通透性增加和炎症,
危重患者的重要死因。几种炎症介质和相关机制
已经确定了肺渗漏增加,这虽然导致了治疗的改进,但已经达到稳定状态,
提示尚未确定的机制和/或不同介质之间的相互作用。在本提案中,我们
建立在我们的初步数据表明,脯氨酸-甘氨酸-脯氨酸(PGP)肽来源于基质,
蛋白质胶原蛋白,在人类和小鼠败血症模型中增加,并且这些基质因子促进肺
通过CXCR 2激活泄漏。在本申请中,我们解决以下三个问题i)什么机制
规范PGP的形成?我们推测,游离血红素,一种新发现的脓毒症发病机制的介质,
刺激含有活性脯氨酰内肽酶(PE)的外泌体的释放,所述活性脯氨酰内肽酶(PE)是一种蛋白酶,
胶原在细胞外室中分解为PGP的终末步骤。初步数据显示
血红素结合素降低体内循环PGP水平; ii)内源性PGP介导脓毒症吗
诱导肺通透性?初步数据显示施用Arg-Thr-Arg(RTR),一种
选择性结合和抑制PGP,在体外和体内防止肺渗漏; iii)PGP是否与肺渗漏的严重程度相关?
人类败血症中的疾病和ALI?初步数据显示,在人类败血症中循环PGP肽增加
并证明这能够引发促渗透性信号传导。我们提出3个目标来检验我们的假设
PGP基质因子介导脓毒症-ALI,SA 1:确定游离血红素的作用和机制
介导PGP肽形成。SA 2:确定PGP介导脓毒症-ALI的作用和机制
和SA 3:确定游离血红素、PE-外来体和PGP肽的血浆水平是否与两者相关。
脓毒症患者的临床结局和肺损伤的发展。我们建议使用以下组合
原代人上皮细胞、肺微血管内皮细胞和盲肠结扎穿孔模型
使用C57 Bl/6雄性和雌性小鼠来测试我们的假设,并将其与生化和
分子方法来测量蛋白酶活性、游离血红素水平、外来体和PGP肽水平。
使用血红素、PGP和产生PGP的蛋白酶的选择性抑制剂将获得机制见解,
以及为所提出的研究产生的新的内皮靶向CXCR 2-/-小鼠模型。成功
这些目标的完成将显著提高我们对脓毒症-ALI的潜在机制的理解,
特别强调含有蛋白酶的外泌体和基质因子作为新的介质和治疗靶点
在这种令人衰弱的疾病中。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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{{ truncateString('AMIT GAGGAR', 18)}}的其他基金
Neutrophil Exosomes: New Pathogenic Entities in COPD
中性粒细胞外泌体:慢性阻塞性肺病的新致病实体
- 批准号:
10657577 - 财政年份:2020
- 资助金额:
$ 54.72万 - 项目类别:
Role of heme and PGP matrikines in lung inflammation
血红素和 PGP 基质素在肺部炎症中的作用
- 批准号:
10693865 - 财政年份:2020
- 资助金额:
$ 54.72万 - 项目类别:
Neutrophil Exosomes: New Pathogenic Entities in COPD
中性粒细胞外泌体:慢性阻塞性肺病的新致病实体
- 批准号:
10480885 - 财政年份:2020
- 资助金额:
$ 54.72万 - 项目类别:
Role of heme and PGP matrikines in lung inflammation
血红素和 PGP 基质素在肺部炎症中的作用
- 批准号:
10028641 - 财政年份:2020
- 资助金额:
$ 54.72万 - 项目类别:
Role of heme and PGP matrikines in lung inflammation
血红素和 PGP 基质素在肺部炎症中的作用
- 批准号:
10247734 - 财政年份:2020
- 资助金额:
$ 54.72万 - 项目类别:
Neutrophil Exosomes: New Pathogenic Entities in COPD
中性粒细胞外泌体:慢性阻塞性肺病的新致病实体
- 批准号:
10467984 - 财政年份:2020
- 资助金额:
$ 54.72万 - 项目类别:
Prolyl Endopeptidase-Mediated Matrix Remodeling and Inflammation in COPD
脯氨酰内肽酶介导的慢性阻塞性肺病基质重塑和炎症
- 批准号:
8734624 - 财政年份:2014
- 资助金额:
$ 54.72万 - 项目类别:
A novel proteolytic system of pulmonary inflammation
肺部炎症的新型蛋白水解系统
- 批准号:
7992739 - 财政年份:2010
- 资助金额:
$ 54.72万 - 项目类别:
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肺生物学和转化医学培训项目
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10442539 - 财政年份:2010
- 资助金额:
$ 54.72万 - 项目类别:
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肺生物学和转化医学培训计划
- 批准号:
9756439 - 财政年份:2010
- 资助金额:
$ 54.72万 - 项目类别:
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