Ancillary to ABC PICU to study MOD in critically ill children
辅助 ABC PICU 研究危重儿童的 MOD
基本信息
- 批准号:9368869
- 负责人:
- 金额:$ 32.76万
- 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:2017-08-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAdult Respiratory Distress SyndromeAngiopoietin-2BioinformaticsBiologicalBiological AssayBiological MarkersBiologyBloodBlood donorChildClinicalClinical ResearchClinical TrialsCoagulation ProcessCritical IllnessCritically ill childrenDataDevelopmentEnrollmentEnvironmentFunctional disorderFutureGenomicsGenotypeHemeIL8 geneIncidenceInflammationInflammatoryInjuryInterleukin-6IronKnowledgeLeadLinkMeasuresModelingMolecular ProfilingMulti-Institutional Clinical TrialMultiple Organ FailureOrganOrgan failureOutcomePathologicPathway interactionsPatientsPatternPediatric Intensive Care UnitsPlasmaPlasminogen Activator Inhibitor 1PlayProcessProductionPrognostic MarkerPublishingReportingResearch InfrastructureRespiratory SystemRespiratory Tract InfectionsRespiratory tract structureRiskRoleSamplingSepsisSeverity of illnessSuggestionSyndromeTestingThrombomodulinThrombosisTransfusionage effectbasebiomarker developmentcirculating biomarkersextracellulargenetic variantgut microbiomehigh riskimprovedinflammatory markerinsightmicrobialmicrobiomemolecular markermolecular phenotypemortalityneutrophilnew therapeutic targetnext generation sequencingnovelprecision medicinepredictive markertargeted treatment
项目摘要
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.
项目总结/摘要
多器官功能障碍综合征(MODS)是危重病患者常见的并发症,
死亡风险增加近10倍。它是一种“综合征”而不是一种特定的病理实体
其特征在于严重的、全身性的和不受控制的炎症过程。几项临床研究
已经报道了炎症和凝血的改变在危重患者中很常见,
因输注红细胞而恶化。我们已发表和尚未发表的数据表明,
IL-6、IL-8、派-1、Thrombomodulin(TM)和Angiopoietin-2(Ang-2)的水平,以及派-1中的遗传变体
和TM与危重儿童和成人的器官功能障碍和死亡率增加有关。
据报道,由活化的中性粒细胞产生的细胞外陷阱(NET)在以下方面发挥作用:
器官损伤,并且已知从输注的RBC释放的细胞外血红素触发
NET。我们的初步研究表明,在MODS的非幸存儿童中,NETs倾向于增加。
最后,来自健康受试者的血液含有大量细菌基因组物质(微生物组),并且这
循环微生物组有可能导致非感染性炎症,从而导致MODS。
然而,改变炎症和血栓形成的标志物,以及NET和循环微生物组的作用,
尚未在足够数量的危重MODS患儿中进行严格研究。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,
接受RBC输血的儿童,并在输血前和输血后(第1、3和5天)采集生物样本
表征炎症和凝血相关的生物标志物,并检查它们与
NPMODS的发展和死亡率。在Aim 1中,我们将测定血浆水平和表达谱,
选择的标志物(IL-6、IL-8、派-1、TM和Ang-2)和输血后血液流变学变化斜率的相关性,
将使用混合效应模型测试具有NPMODS和死亡率的测量的生物标志物。在目标2中。我们将
基因型标签SNP和测序靶区域,以检测遗传变异并评估其对
生物标志物轨迹和NPMODS的发展以及死亡率。在目标3中,无偏见的下一代
测序后进行非人序列比对将用于鉴定和表征
循环微生物组,我们将测试微生物多样性和负荷与循环的关联。
生物标志物和NPMODS。这项研究将描述预后和预测生物标志物,并提供
建立这些标记物与NPMODS发展之间联系的机制见解。的
获得的知识和由此定义的分子表型可以鉴定新的治疗靶点,
为未来的临床试验提供信息,并导致针对治疗药物的精准医学策略的发展
药物用于具有特定分子表型或生物标志物模式的患者。
项目成果
期刊论文数量(0)
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{{ truncateString('ANIL SAPRU', 18)}}的其他基金
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:
9905545 - 财政年份:2017
- 资助金额:
$ 32.76万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 32.76万 - 项目类别:
Collaborative Research to Validate Biomarkers of Pediatric ARDS
验证儿科 ARDS 生物标志物的合作研究
- 批准号:
8857732 - 财政年份:2014
- 资助金额:
$ 32.76万 - 项目类别:
Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial
儿科胰岛素滴定试验中的凝血和纤溶
- 批准号:
8690137 - 财政年份:2012
- 资助金额:
$ 32.76万 - 项目类别:
Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial
儿科胰岛素滴定试验中的凝血和纤溶
- 批准号:
8517183 - 财政年份:2012
- 资助金额:
$ 32.76万 - 项目类别:
Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial
儿科胰岛素滴定试验中的凝血和纤溶
- 批准号:
8415716 - 财政年份:2012
- 资助金额:
$ 32.76万 - 项目类别:
Targeted Genomic Analysis of Coagulation Pathways in Acute Lung Injury
急性肺损伤凝血途径的靶向基因组分析
- 批准号:
7904846 - 财政年份:2007
- 资助金额:
$ 32.76万 - 项目类别:
Targeted Genomic Analysis of Coagulation Pathways in Acute Lung Injury
急性肺损伤凝血途径的靶向基因组分析
- 批准号:
7663875 - 财政年份:2007
- 资助金额:
$ 32.76万 - 项目类别:
Targeted Genomic Analysis of Coagulation Pathways in Acute Lung Injury
急性肺损伤凝血途径的靶向基因组分析
- 批准号:
7478459 - 财政年份:2007
- 资助金额:
$ 32.76万 - 项目类别:
Targeted Genomic Analysis of Coagulation Pathways in Acute Lung Injury
急性肺损伤凝血途径的靶向基因组分析
- 批准号:
7318993 - 财政年份:2007
- 资助金额:
$ 32.76万 - 项目类别:
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