Interleukin-1 Receptor Antagonist in ARDS

ARDS 中的 IL-1 受体拮抗剂

基本信息

批准号：
9130417
负责人：
Nuala Jennings Meyer
金额：
$ 61.42万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130417
关键词：
Accounting Address Adult Respiratory Distress Syndrome Alleles American Animals C-reactive protein Cardiovascular system Clinical Trials Cohort Studies Complication Critical Illness Data Detection Development Dose Endotoxemia Endotoxins Etiology Foundations Future Gametogenesis Generic Drugs Genes Genetic Genetic Determinism Genetic Markers Genotype Health Human Human Volunteers IL1R1 gene Immune In Vitro Incidence Inflammation Inflammatory Interleukin-1 Interleukin-1 beta Interleukins Intravenous Knowledge LDL Cholesterol Lipoproteins Medical Modeling Molecular Molecular Profiling Monitor Names Nature Outcome Pathologic Patient Selection Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Placebos Plasma Population Predisposition Prevention Proteins Public Health Quantitative Trait Loci Randomized Randomized Controlled Trials Recombinants Regulation Risk Role Sampling Sepsis Severity of illness Shock Single Nucleotide Polymorphism Specimen Stimulus Stress Stress Tests Subgroup Supportive care Syndrome Testing Variant adverse outcome anakinra base cohort cytokine effective therapy genetic association genetic profiling genetic variant genome-wide healthy volunteer improved mortality novel personalized medicine precision medicine prevent protein complex protein expression randomized trial research study response septic therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) is a common and devastating complication of severe sepsis carrying a very high mortality. ARDS lacks any effective pharmacotherapy. We previously described a functional genetic variant in the interleukin-1 receptor antagonist gene, encoding the protein IL1RA, which associates with reduced ARDS risk, improved sepsis survival, and with higher plasma IL1RA. A recombinant form of IL1RA (anakinra) has been suggested as a possible therapy for severe sepsis, the most common precipitant of ARDS, though the effect was modest and predictors of anakinra response are lacking. Our preliminary data raises the possibility that anakinra would be a helpful therapy in ARDS. This application will address whether anakinra may show promise as a preventative agent or a therapy in ARDS and whether response to anakinra may be predicted by genetic or molecular profiles. In aim 1, we will infer the causality of early plasma IL1RA level for ARDS susceptibility, and the causality of interleukin-1 beta (IL1ß) for ARDS mortality, using genotype as an instrumental variable that explains a large proportion of each plasma marker's variance. If these markers seem to be causal for ARDS or mortality, then targeting them with anakinra is a logical next step. In aim 2, we identify the functional genetic determinants of evoked plasma IL1RA using a human endotoxin model to stimulate inflammatory stress, and test functional variants for association with sepsis-associated ARDS. In aim 3, we molecularly characterize plasma stored from the last randomized controlled trial of anakinra in severe sepsis, to test whether plasma cytokine level or genotype can define a subgroup of patients who had reduced mortality with anakinra. This proposal uses 3 novel human populations to address the role of IL1RA in sepsis-associated ARDS: a large cohort of critically ill subjects with severe sepsis monitored for ARDS; an experimental human volunteer pool given intravenous endotoxin as a stimulus for inflammatory stress; and a completed clinical trial population with severe sepsis who were randomized to receive placebo or anakinra. Completion of this project will yield new knowledge regarding the potential role of recombinant IL1RA to prevent or treat ARDS, and may identify an ideal clinical trial population for future testing of personalized IL1RA therapy.

描述（由适用提供）：急性呼吸窘迫综合征（ARDS）是严重败血症的常见且破坏性的并发症，具有很高的死亡率。 Ards缺乏任何有效的药物疗法。我们先前描述了白细胞介素-1受体拮抗剂基因中的功能性遗传变异，编码蛋白IL1RA，该蛋白IL1RA与ARDS风险降低，败血症的存活率改善并与较高的血浆IL1RA相关联。已经提出了一种重组形式的IL1RA（Anakinra）作为严重败血症的一种可能的疗法，这是最常见的ARDS沉淀物，尽管其效果是适度的，并且缺乏Anakinra反应的预测指标。我们的初步数据增加了Anakinra成为ARDS的有用疗法的可能性。该应用将解决Anakinra是否可以表现出作为预防剂或ARDS治疗的希望，以及是否可以通过遗传或分子特征来预测对Anakinra的反应。在AIM 1中，我们将使用Genotype作为一种仪器变量来推断ARDS敏感性早期血浆IL1RA水平的偶然性以及白介素-1β（IL1ß）的偶然性，以解释每个血浆标志物的差异的很大比例。如果这些标记似乎是ARDS或死亡率的因果关系，那么将它们靶向Anakinra是合乎逻辑的下一步。在AIM 2中，我们使用人内毒素模型来鉴定诱发血浆IL1RA的功能性遗传决定剂，以刺激炎症应激，并测试功能变异，以与脓毒症相关的ARDS结合。在AIM 3中，我们的分子表征了从严重败血症中Anakinra的最后一次随机对照试验中存储的血浆，以测试血浆细胞因子水平还是基因型是否可以定义降低Anakinra死亡率的患者的亚组。 3个新的人类种群来解决IL1RA在败血症相关的ARDS中的作用：大量重病受试者与严重的败血症监测了ARDS；一个实验性的人类志愿者池将静脉内内毒素作为炎症应激的刺激。和完整的临床试验人群患有严重败血症，他们被随机接受安慰剂或阿纳基纳拉。该项目的完成将产生有关重组IL1RA预防或治疗ARDS的潜在作用的新知识，并可能确定理想的临床试验人群，以未来对个性化IL1RA治疗的测试。