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

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 IL1to 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 IL1for 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) 是一种危及生命的空域炎症性疾病, 水肿导致严重低血氧水平,这可能会使 24% 的 ICU 入院情况复杂化 机械通气的死亡率仍然高于 35%,并且没有预防或药物治疗选择。 先前鉴定并复制了白细胞介素 1 受体拮抗剂 (IL1RA) 的功能性遗传变异 基因,编码蛋白质 IL1RA,与较低的 ARDS 风险和较高的诱发因素密切相关 我们还证明了血浆白细胞介素 1 β (IL1)(该分子)的因果作用。 最后,在随机接受治疗的受试者亚组中,IL1RA 抑制了败血性休克的死亡率。 我们证明重组人白细胞介素 1 受体拮抗剂 (rhIL1RA) 或脓毒症安慰剂 rhIL1RA 的死亡率治疗效果存在显着异质性,可通过血浆 IL1RA 进行预测 总而言之,我们的数据表明,一些患者可能受到基因保护,免受 ARDS 的侵害。 通过更有效的 IL1RA 生产,表明药物 rhIL1RA 可能是一种有效的预防或治疗方法。 然而,由于我们证明rhIL1RA在脓毒症期间的作用并不统一,因此 当前的应用程序将获得有关血浆 IL1RA 和 IL1 的因果贡献的关键信息 ARDS 风险和 ARDS 导致的死亡,将开发 ARDS 风险的预测模型,以确定目标 rhIL1RA 干预的人群,并将确定 rhIL1RA 治疗对离体的直接影响 我们的长期目标是评估 rhIL1RA 作为一种精确的 ARDS 预防和/或治疗方法。 目标 1 将重点关注 ARDS 风险,使用遗传工具变量技术来推断 ARDS 风险。 血浆 IL1RA 和 IL1对 ARDS 风险的因果影响,以及开发和验证 ARDS 预测 考虑 2 个大型脓毒症队列中的临床因素和血浆 IL-1 标记物的模型目标 2 将重点关注。 我们将使用多种基因型作为工具变量来测试其贡献。 早期或延迟血浆 IL-1 标记物与 ARDS 死亡相关,并将开发和验证预测模型 对于 ARDS 死亡率,使用在 2 个大型脓毒症队列中测量的临床数据和血浆 IL-1 标记物。 我们将使用一种称为离体肺灌注(EVLP)的新型平台,因此肺功能下降了 移植在高度控制的环境中进行通风和灌注,以测试是否给予rhIL1RA 因为治疗或预防受伤的人类肺部将改善氧合、肺顺应性和 制定这些目标的多学科研究人员和顾问团队包括 EVLP。 专家,2 名流行病学家,具有肺损伤预测和分子亚表型、统计方面的专业知识 遗传学家是工具变量分析方面的专家,PI 是一位转化科学家,他首先发现了 IL1RN 变异、血浆蛋白表达和 ARDS 风险之间的联系。

项目成果

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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:
Interleukin-1 Receptor Antagonist in ARDS
ARDS 中的 IL-1 受体拮抗剂
  • 批准号:
    9130417
  • 财政年份:
    2015
  • 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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