Novel diagnostic and stratification tools for septic shock

感染性休克的新型诊断和分层工具

• 批准号: 8695557
• 负责人: HECTOR R. WONG
• 金额: $ 50.36万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695557
• 关键词: Accident and Emergency department; Address; Adrenal Cortex Hormones; Adult; Bacterial Infections; Biological Markers; Blood; Cessation of life; Child; Child health care; Childhood; Clinical; Clinical Assessment Tool; Clinical Data; Clinical Management; Clinical Research; Clinical Trials; Complex; Conduct Clinical Trials; Critical Care; Critical Illness; Critically ill children; DNA; Data; Databases; Decision Making; Development; Diagnosis; Diagnostic; Enrollment; Evolution; Failure; Fever; Flow Cytometry; Foundations; Funding; Gene Expression; Genes; Genome; Glucocorticoid Receptor; Glucocorticoids; Goals; Hospitals; Immune response; Individual; Inflammation; Intensive Care Units; Interleukins; Investigational Therapies; Laboratories; Link; Measurement; Measures; Medicine; Messenger RNA; Methods; Metric; Mining; Modeling; Organ failure; Outcome; Patients; Phase; Population; Predictive Value; Proteins; Protocols documentation; Public Health; RNA; Receptor Signaling; Recruitment Activity; Repression; Research; Risk; Role; Sampling; Sepsis Syndrome; Septic Shock; Serum; Serum Proteins; Severity of illness; Signal Pathway; Signaling Pathway Gene; Specificity; Statistical Models; Sterility; Stratification; Testing; Time; Translational Research; United States; United States National Institutes of Health; Whole Blood; base; biobank; clinical phenotype; clinical practice; cohort; digital; gene repression; genome-wide; improved; innovation; insight; mRNA Expression; mortality; novel; novel diagnostics; pre-clinical; procalcitonin; programs; public health relevance; randomized trial; receptor expression; tool; transcriptomics

DESCRIPTION (provided by applicant): Septic shock continues to be a major public health problem in both adults and children. An important and unmet clinical gap in the field is the lack of robust stratification and diagnostic tools specific for septic shock. This proposal seeks to directly address this gap. We have leveraged our extensive, multi-center gene expression databank of children with septic shock to identify gene signatures that provide a strong foundation for the development of novel stratification and diagnostic tools for clinical septic shock. The major innovation of this proposal is the ability to directly leverage transcriptomic dat as a basis for clinical advancements, an often stated, but seldom achieved goal of transcriptomics. We are proposing three independent, but highly complementary Specific Aims, all of which directly address the aforementioned, unmet clinical gap. In Specific Aim 1, we will test the hypothesis that the mRNA expression of 84 genes can enhance the accuracy of an existing, validated model to stratify more reliably the risk of death or survival in children with septic shock. We have identified 84 candidate stratification genes having predictive capacity of mortality/survival. Using a digital mRNA measurement platform, we will incorporate the mRNA expression data from these 84 genes to enhance the predictive capacity of a recently developed, serum protein biomarker-based model. The enhanced model will be derived in an existing cohort of 300 patients, and subsequently validated in a prospectively enrolled cohort of 200 patients. In Specific Aim 2, we will test the hypothesis that interleukin-27 can serve as a diagnostic biomarker for bacterial infection. We have identified IL-27 as a candidate diagnostic biomarker for bacterial infection. In a cohort of critically ill children, we have demonstrated tha IL-27 serum protein concentrations can predict bacterial infection with a specificity and positive predictive value of >90%. We will further test the ability of serum IL-27 protein concentration to serve as a diagnostic biomarker in two separate cohorts of patients recruited from the Emergency Department and the Intensive Care Unit. In Specific Aim 3, we will test the hypothesis that there exists a group of patients with septic shock characterized by decreased expression of the glucocorticoid receptor (GCR). Our gene expression data have identified a group of patients with septic shock who are characterized by widespread repression of genes corresponding to the GCR signaling pathway, and this particular group of patients has higher illness severity and mortality, compare to two other groups without repression of GCR signaling pathway genes. This suggests the existence of an identifiable group of patients with septic shock who are relatively less responsive to adjunctive glucocorticoids. If this holds true, it woul represent a major confounder for studying the role of adjunctive corticosteroids for septic shock, which is currently a major controversy in the field. We have developed a flow cytometry-based protocol to directly measure GCR expression in the blood compartment of patients with septic shock. We will systematically measure GCR expression and correlate GCR expression with clinical phenotypes. Collectively, these three Aims have the potential to substantially advance the stratification and diagnostic armamentarium for clinical septic shock.

描述（由申请人提供）：在成年人和儿童中，败血性休克仍然是一个主要的公共卫生问题。该领域的一个重要且未满足的临床差距是缺乏特异性化败血性休克的稳健分层和诊断工具。该提案旨在直接解决这一差距。我们利用了具有败血性休克儿童的广泛的，多中心的基因表达数据库，以识别基因特征，为开发新的分层和诊断工具提供了临床败血性休克的基础。该提案的主要创新是能够直接利用转录组DAT作为临床进步的基础的能力，这是经常说明的，但很少实现转录组学的目标。我们提出了三个独立但高度互补的特定目的，所有目标都直接解决了上述未经修复的临床差距。在特定的目标1中，我们将检验以下假设：84个基因的mRNA表达可以提高现有的，经过验证的模型的准确性，以更可靠地分层败血性休克儿童死亡或生存的风险。我们已经确定了具有死亡率/生存性预测能力的84个候选分层基因。使用数字mRNA测量平台，我们将合并来自这84个基因的mRNA表达数据，以增强基于血清蛋白质生物标志物模型的预测能力。增强模型将得出300例现有的队列中，并随后在前瞻性招募的200名患者的队列中进行了验证。在特定目标2中，我们将测试白介素27可以作为细菌感染的诊断生物标志物的假设。我们已经确定IL-27是细菌感染的候选诊断生物标志物。在一系列重症儿童中，我们已经证明了IL-27血清蛋白浓度可以预测具有特异性和阳性预测值> 90％的细菌感染。我们将进一步测试血清IL-27蛋白浓度在两名独立的从急诊科和重症监护室招募的患者中作为诊断生物标志物的能力。在特定目标3中，我们将检验一组具有败血性休克患者的假设，其特征是糖皮质激素受体（GCR）的表达降低。我们的基因表达数据已经确定了一组具有败血性休克的患者，这些患者的特征是对与GCR信号通路相对应的基因广泛抑制，并且这组特定的患者具有较高的疾病严重性和死亡率，与其他两组相比，没有GCR信号途径的抑制。这表明存在一组可识别的败血性休克患者，这些患者对辅助糖皮质激素的反应相对较少。如果这是真的，它将代表研究辅助性皮质类固醇对败血性休克的作用的主要混杂因素，这是该领域的主要争议。我们已经开发了一种基于流式细胞仪的方案，可以直接测量败血性休克患者血室中的GCR表达。我们将系统地测量GCR表达并将GCR表达与临床表型相关。总体而言，这三个目标有可能大大推动分层和诊断疗法的临床性休克。