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（由申请人提供）：急性呼吸窘迫综合征（ARDS）是严重脓毒症的一种常见且具有破坏性的并发症，死亡率非常高。我们之前描述了白细胞介素-1受体拮抗剂的功能性遗传变异。基因，编码蛋白质 IL1RA，与降低 ARDS 风险、改善脓毒症生存率以及较高的血浆 IL1RA 相关，有人建议将重组形式的 IL1RA（阿那白滞素）作为一种可能的治疗方法。对于严重脓毒症（ARDS 最常见的诱发因素），尽管效果不大并且缺乏阿那白滞素反应的预测因子，但我们的初步数据表明阿那白滞素可能是 ARDS 的一种有效疗法。 ARDS 的预防剂或治疗方法是否可以通过遗传或分子谱预测阿那白滞素及其反应在目标 1 中，我们将推断早期血浆 IL1RA 水平与 ARDS 的因果关系。易感性以及白细胞介素 1 β (IL1ß) 与 ARDS 死亡率的因果关系，使用基因型作为工具变量来解释每个血浆标记物变异的很大一部分。如果这些标记物似乎与 ARDS 或死亡率有关，则将其作为目标。阿那白滞素是合乎逻辑的下一步，在目标 2 中，我们使用人内毒素模型来刺激炎症应激，以确定诱发血浆 IL1RA 的功能遗传决定因素，并测试与脓毒症相关的功能变异。在目标 3 中，我们对上次阿那白滞素治疗严重脓毒症的随机对照试验中储存的血浆进行分子特征分析，以测试血浆细胞因子水平或基因型是否可以定义使用阿那白滞素降低死亡率的患者亚组。人群以解决 IL1RA 在脓毒症相关 ARDS 中的作用：对一大群患有严重脓毒症的危重受试者进行 ARDS 监测，并给予静脉注射内毒素作为炎症应激刺激；患有严重脓毒症的临床试验人群被随机接受安慰剂或阿那白滞素治疗，该项目的完成将产生关于重组 IL1RA 在预防或治疗 ARDS 中的潜在作用的新知识，并可能确定用于未来个性化 IL1RA 测试的理想临床试验人群。治疗。