Ancillary to ABC PICU to study MOD in critically ill children

辅助 ABC PICU 研究危重儿童的 MOD

• 批准号: 9534163
• 负责人: ANIL SAPRU
• 金额: $ 39.38万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9534163
• 关键词: Adult; Adult Respiratory Distress Syndrome; Angiopoietin-2; Bioinformatics; Biological; Biological Assay; Biological Markers; Biology; Blood; Blood donor; Child; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Critical Illness; Critically ill children; Data; Development; Enrollment; Environment; Expression Profiling; Functional disorder; Future; Genomics; Genotype; Heme; IL8 gene; Incidence; Inflammation; Inflammatory; Injury; Interleukin-6; Iron; Knowledge; Lead; Link; Measures; Modeling; Multi-Institutional Clinical Trial; Multiple Organ Failure; Organ; Organ failure; Outcome; Pathologic; Pathway interactions; Patients; Pattern; Pediatric Intensive Care Units; Plasma; Plasminogen Activator Inhibitor 1; Play; Process; Production; Prognostic Marker; Publishing; Reporting; Research Infrastructure; Respiratory System; Respiratory Tract Infections; Risk; Role; Sampling; Sepsis; Severity of illness; Suggestion; Syndrome; Testing; Thrombomodulin; Thrombosis; Transfusion; age effect; base; biomarker development; circulating biomarkers; extracellular; genetic variant; gut microbiome; high risk; improved; inflammatory marker; insight; microbial; microbiome; microbiome alteration; molecular marker; molecular phenotype; mortality; neutrophil; new therapeutic target; next generation sequencing; novel; precision medicine; predictive marker; targeted treatment

PROJECT SUMMARY/ABSTRACT Multiple Organ Dysfunction Syndrome (MODS) occurs frequently in the setting of critical illnesses and is associated with a nearly 10-fold higher mortality risk. It is a “syndrome” rather than a specific pathological entity that is characterized by a severe, systemic, and uncontrolled inflammatory process. Several clinical studies have reported that alterations in inflammation and coagulation are common in critically ill patients and may be worsened by transfusion of RBCs. Our published and yet to be published data suggest that higher plasma levels of IL-6, IL-8, PAI-1, Thrombomodulin (TM), and Angiopoietin -2 (Ang-2), and genetic variants in PAI-1 and TM are associated with increased organ dysfunction and mortality in critically ill children and adults. Neutrophil Extracellular Traps (NETs), produced by activated neutrophils, have been reported to play a role in organ injury, and extracellular heme released from transfused RBCs is known to trigger the production of NETs. Our preliminary studies suggest that NETs tend to be increased in non-survivor children with MODS. Finally, blood from healthy subjects contains a host of bacterial genomic material (microbiome) and this circulating microbiome has the potential to lead to non-infectious inflammation, thereby contributing to MODS. However, markers of altered inflammation and thrombosis, and the role of NETs and circulating microbiome have not yet been studied rigorously in a sufficient number of critically ill children with MODS. We propose to leverage the infrastructure of the ABC PICU study, an ongoing multi-center clinical trial to enroll critically ill children undergoing RBC transfusions and collect biological samples pre- and post-transfusion (day 1, 3 and 5) to characterize inflammation and coagulation related biomarkers and examine their relationship to the development of NPMODS and mortality. In Aim1, we will assay plasma levels and expression profile of selected markers (IL-6, IL-8, PAI-1,TM and Ang-2) and association of post-transfusion slope of change in the measured biomarkers with NPMODS and mortality will be tested using mixed effect models. In Aim 2. we will genotype tag SNPs and sequence target regions to detect genetic variants and assess their effect on biomarker trajectories and development of NPMODS and mortality. In Aim 3, unbiased next generation sequencing followed by alignment of non-human sequences will be used to identify and characterize the circulating microbiome and we will test for association of microbial diversity and burden with circulating biomarkers and NPMODS. This study will characterize prognostic and predictive biomarkers and provide mechanistic insights that establish a link between these markers and the development of NPMODS. The knowledge acquired and molecular phenotypes thus defined may identify novel therapeutic targets, and will inform future clinical trials and lead to development of precision medicine strategies targeting therapeutic agents to patients with specific molecular phenotypes or biomarker patterns.

项目摘要/摘要 多个器官功能障碍综合征（MOD）经常发生在重症疾病的情况下，IS 与死亡率的风险高近10倍。它是“综合征”，而不是特定的病理实体 其特征是严重，系统性和不受控制的炎症过程。几项临床研究 已经报告说，炎症和凝结的改变在重症患者中很常见，可能是 RBC的输血使人恶化。我们已发布且尚未发布的数据表明，血浆较高 PAI-1 和TM与重症儿童和成人的器官功能障碍和死亡率的增加有关。 据报道，由激活的中性粒细胞产生的中性粒细胞外陷阱（网）在 已知器官损伤和从输血的RBC释放的细胞外血红素会触发产生 网。我们的初步研究表明，非幸存的MOD儿童往往会增加网。 最后，健康受试者的血液中包含大量细菌基因组材料（微生物组），这 循环微生物组有可能导致非感染感染，从而导致mod。 但是，注射和血栓形成改变的标记以及网和循环微生物组的作用 尚未在有足够数量的患有mod的危重儿童中进行严格研究。我们建议 利用ABC PICU研究的基础设施，这是一项正在进行的多中心临床试验，以注册重病 接受RBC输血的儿童并收集转移前和转化后的生物样品（第1、3和5天） 表征炎症和凝结相关的生物标志物并检查其与 NPMOD和死亡率的发展。在AIM1中，我们将主张血浆水平和表达曲线 选定的标记（IL-6，IL-8，PAI-1，TM和ANG-2）以及转移后变化斜率的关联 具有NPMOD和死亡率的测量生物标志物将使用混合效应模型进行测试。在AIM 2中。我们将 基因型TAG SNP和序列目标区域以检测遗传变异并评估其对 生物标志物轨迹和NPMOD和死亡率的发展。在AIM 3中，公正的下一代 测序之后进行非人类序列的比对将用于识别和表征 循环微生物组，我们将测试微生物多样性的关联，并随着循环 生物标志物和NPMods。这项研究将表征预后和预测性生物标志物，并提供 机械洞察力在这些标记与NPMOD的发展之间建立联系。 获得的知识和这样定义的分子表型可以识别新的治疗靶标，并且将 告知未来的临床试验并导致针对治疗的精确医学策略的发展 具有特定分子表型或生物标志物模式的患者的药物。