Reconsidering the IL-1 axis in sepsis-associated ARDS
重新考虑败血症相关 ARDS 中的 IL-1 轴
基本信息
- 批准号:9922370
- 负责人:
- 金额:$ 47.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-15 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAdmission activityAdult Respiratory Distress SyndromeAllelesAmericanAttenuatedAwardBiological MarkersBloodCessation of lifeClinicalClinical DataClinical MarkersClinical TrialsCodeControlled EnvironmentDataDevelopmentEdemaEndotoxinsEpidemiologistEtiologyFailureFundingFutureGenesGeneticGenotypeGoalsHeterogeneityHourHumanHypoxiaIndividualInflammationInjuryInterleukin-1Interleukin-1 betaInterventionIntervention TrialKnowledgeLifeLinkLungLung ComplianceManuscriptsMeasuresMechanical ventilationMessenger RNAModelingModernizationMolecularMolecular ProfilingOxygenPathway interactionsPatientsPerfusionPermeabilityPharmaceutical PreparationsPharmacotherapyPhysiologicalPlacebosPlasmaPlasma ProteinsPlayPopulationPreventionPrevention strategyProductionRandomizedRecombinantsResearch PersonnelRiskRoleSafetySepsisSeptic ShockSubgroupSystemTarget PopulationsTechniquesTestingTranslatingTransplantationVariantVentilatorWorkanakinracohortcytokinedesigngenetic analysisgenetic variantimprovedindividualized preventioninjuredlung injurymembermortalitymortality riskmultidisciplinarynovelpatient populationpersonalized interventionprecision medicinepreclinical efficacypredictive modelingpreventprotein expressionseptictargeted treatmenttooltranslational scientisttreatment effecttreatment strategy
项目摘要
The acute respiratory distress syndrome (ARDS) is a life-threatening condition of airspace inflammation and
edema causing severely low blood oxygen levels that may complicate up to 24% of ICU admissions for
mechanical ventilation. Mortality remains above 35% and no prevention or pharmacotherapy options exist. We
previously identified and replicated a functional genetic variant in the interleukin-1 receptor antagonist (IL1RA)
gene, encoding the protein IL1RA, that was strongly associated with lower ARDS risk and higher evoked
plasma IL1RA levels. We also demonstrated a causal role for plasma interleukin-1 beta (IL1), the molecule
inhibited by IL1RA, in mortality from septic shock. Finally, in a subgroup of subjects randomized to receive
recombinant human interleukin-1 receptor antagonist (rhIL1RA) or placebo for sepsis, we demonstrated
significant heterogeneity in the mortality treatment effect of rhIL1RA that was predictable by plasma IL1RA
concentration. Taken together, our data indicated that some patients may be genetically protected from ARDS
via more efficient IL1RA production, suggesting that the drug rhIL1RA may be an effective prevention or
treatment strategy. However, because we proved that the effect of rhIL1RA during sepsis is not uniform, the
current application will obtain critical information about the causal contribution of plasma IL1RA and IL1to
ARDS risk and death from ARDS, will develop predictive models for ARDS risk in an effort to identify a target
population for rhIL1RA intervention, and will determine the direct effects of rhIL1RA treatment on ex vivo
perfused human lungs. Our long term objective is to evaluate rhIL1RA as a precision ARDS prevention and/or
treatment strategy. Aim 1 will focus on ARDS risk, using a genetic instrumental variable technique to infer the
causal effect of plasma IL1RA and IL1for ARDS risk, and developing and validating an ARDS predictive
model that considers clinical factors and plasma IL-1 markers in 2 large sepsis cohorts. Aim 2 will focus on
ARDS and sepsis mortality. We will use multiple genotypes as an instrumental variable to test the contribution
of early or delayed plasma IL-1 markers for death from ARDS, and will develop and validate predictive models
for ARDS mortality, using clinical data and plasma IL-1 markers measured in 2 large sepsis cohorts. In Aim 3,
we will use a novel platform known as ex vivo lung perfusion (EVLP), whereby lungs declined for
transplantation are ventilated and perfused in a highly controlled environment, to test whether rhIL1RA given
as treatment or prevention to injured human lungs will improve oxygenation, lung compliance, and
inflammation. The multidisciplinary team of investigators and consultants to enact these aims include an EVLP
expert, 2 epidemiologists with expertise in lung injury prediction and molecular subphenotyping, a statistical
geneticist who is expert in instrumental variable analysis, and the PI, a translational scientist who first identified
a link between IL1RN variation, plasma protein expression, and ARDS risk.
急性呼吸窘迫综合征(ARDS)是空域注射和
水肿导致严重低血氧水平,可补充多达24%的ICU入院
机械通气。死亡率仍高于35%,没有预防或药物治疗方案。我们
先前鉴定并复制了白介素-1受体拮抗剂(IL1RA)中的功能性遗传变异
编码蛋白质IL1RA的基因与较低的ARDS风险密切相关,并唤起较高
血浆IL1RA水平。我们还证明了血浆白介素-1β(IL1)的因果作用,分子
被IL1RA抑制,因败血性休克而死亡。最后,在随机接收的受试者子组中
重组人白细胞介素-1受体拮抗剂(Rhil1ra)或安慰剂用于败血症,我们证明了
血浆IL1RA可预测的Rhil1RA死亡率治疗效应的显着异质性
专注。综上所述,我们的数据表明某些患者可以受到遗传保护
通过更有效的IL1RA生产,表明该药物Rhil1ra可能是有效的预防或
治疗策略。但是,因为我们证明了败血症期间rhil1ra的作用并不统一,所以
当前的应用将获得有关等离子体IL1RA和IL1的因果贡献的关键信息
ARDS的风险和ARDS死亡将开发针对ARDS风险的预测模型,以确定目标
RHIL1RA干预的种群,并将确定Rhil1ra治疗对离体的直接影响
灌注的人肺。我们的长期目标是评估Rhil1ra作为预防和/或
治疗策略。 AIM 1使用遗传仪器变量技术来推断ARDS风险
等离子体IL1RA和IL1的因果效应,以产生ARDS风险,并发展和验证ARDS预测性
模拟了在2个大型败血症队列中考虑临床因素和血浆IL-1标记的模型。 AIM 2将重点关注
ARDS和败血症死亡率。我们将使用多种基因型作为仪器变量来测试贡献
ARDS死亡的早期或延迟等离子体IL-1标记,并将开发和验证预测模型
对于ARDS死亡率,使用临床数据和等离子IL-1标记在2个大型败血症同类中测得的。在AIM 3中,
我们将使用一个名为Ex Vivo肺部灌注(EVLP)的新型平台,肺部下降了
移植在高度控制的环境中通风和灌注,以测试Rhil1ra是否给予
由于对受伤的人肺的治疗或预防将改善氧合,肺合顺顺和
炎。颁布这些目标的调查人员和顾问的多学科团队包括EVLP
专家,2名具有肺损伤预测专家的流行病学家和分子亚型型,统计
是仪器变量分析专家的通用者,而PI是翻译科学家,他首先确定
IL1RN变异,血浆蛋白表达和ARDS风险之间的联系。
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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Nuala Jennings Meyer其他文献
Nuala Jennings Meyer的其他文献
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{{ truncateString('Nuala Jennings Meyer', 18)}}的其他基金
Investigating Individual Susceptibility and Host Response in Acute Respiratory Distress Syndrome
研究急性呼吸窘迫综合征的个体易感性和宿主反应
- 批准号:
10686805 - 财政年份:2022
- 资助金额:
$ 47.37万 - 项目类别:
Investigating Individual Susceptibility and Host Response in Acute Respiratory Distress Syndrome
研究急性呼吸窘迫综合征的个体易感性和宿主反应
- 批准号:
10353311 - 财政年份:2022
- 资助金额:
$ 47.37万 - 项目类别:
Reconsidering the IL-1 axis in sepsis-associated ARDS
重新考虑败血症相关 ARDS 中的 IL-1 轴
- 批准号:
9364772 - 财政年份:2017
- 资助金额:
$ 47.37万 - 项目类别:
Genetic Variation in the ANGPT-TIE Pathway and Risk for Acute Lung Injury
ANGPT-TIE 通路的遗传变异和急性肺损伤的风险
- 批准号:
8450810 - 财政年份:2010
- 资助金额:
$ 47.37万 - 项目类别:
Genetic Variation in the ANGPT-TIE Pathway and Risk for Acute Lung Injury
ANGPT-TIE 通路的遗传变异和急性肺损伤的风险
- 批准号:
8650308 - 财政年份:2010
- 资助金额:
$ 47.37万 - 项目类别:
Genetic Variation in the ANGPT-TIE Pathway and Risk for Acute Lung Injury
ANGPT-TIE 通路的遗传变异和急性肺损伤的风险
- 批准号:
8242724 - 财政年份:2010
- 资助金额:
$ 47.37万 - 项目类别:
Genetic Variation in the ANGPT-TIE Pathway and Risk for Acute Lung Injury
ANGPT-TIE 通路的遗传变异和急性肺损伤的风险
- 批准号:
8053876 - 财政年份:2010
- 资助金额:
$ 47.37万 - 项目类别:
Genetic Variation in the ANGPT-TIE Pathway and Risk for Acute Lung Injury
ANGPT-TIE 通路的遗传变异和急性肺损伤的风险
- 批准号:
7877203 - 财政年份:2010
- 资助金额:
$ 47.37万 - 项目类别:
Role of Growth Arrest and DNA Damage 45-alpha in Acute Lung Injury Pathogenesis
生长停滞和 DNA 损伤 45-α 在急性肺损伤发病机制中的作用
- 批准号:
7276255 - 财政年份:2007
- 资助金额:
$ 47.37万 - 项目类别:
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