Stratification of pediatric septic shock

小儿感染性休克的分层

• 批准号: 8366660
• 负责人: HECTOR R. WONG
• 金额: $ 37.31万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-07 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366660
• 关键词: Ablation; Address; Admission activity; Adult; Biological; Biological Markers; Biology; Candidate Disease Gene; Child; Child health care; Childhood; Classification; Clinical; Clinical Data; Clinical Management; Clinical Research; Clinical Trials; Collaborations; Creatinine; Critical Illness; DNA; DNA Databases; Data; Databases; Derivation procedure; Development; Early Diagnosis; Early treatment; Enrollment; Failure; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic; Genome; Genomics; Genotype; Glucocorticoid Receptor; Gold; Heterogeneity; Hour; Infection; Intensive Care Units; Kidney Failure; Lead; Measurement; Measures; Messenger RNA; Metalloproteases; Microarray Analysis; Modeling; Molecular Profiling; Neutrophil Collagenase; Patients; Pattern Recognition; Phase; Physiological; Population; Positioning Attribute; Prevention; Proteins; Public Health; Publishing; Receptor Signaling; Risk; Sampling; Sepsis; Septic Shock; Serum; Serum Proteins; Severity of illness; Shock; Stratification; Syndrome; Testing; Therapeutic; Tissue-Specific Gene Expression; Validation; Variant; adaptive immunity; base; clinically relevant; cohort; design; digital; high risk; inhibitor/antagonist; mortality; nano-string; novel; novel therapeutic intervention; oncology; pre-clinical; prevent; programs; tool

DESCRIPTION (provided by applicant): Septic shock is a major public health problem in both adults and children. Septic shock is a heterogeneous syndrome having highly variable expression in a given patient cohort. A key challenge in the field is to reduce and manage this heterogeneity by more effectively stratifying patients for the purposes of more rational and effective clinical research and individualized clinical management. Over the last 7 years we have developed a genomic expression data base of children with septic shock. We are now proposing to leverage this richly annotated database to develop novel septic shock stratification tools via 3 Specific Aims focused on gene expression-based septic shock subclasses, biomarkers for early detection of septic shock associated renal failure, and genotyping of a novel candidate gene in sepsis biology. In Specific Aim 1 we will derive a classification strategy that groups septic shock patients into distinct subclasses based on a 100 gene expression signature. The classification strategy will be derived in an existing cohort of 180 patients and gene expression measurements will be conducted using the NanoString nCounter platform. Based on our recently published data, we expect that the expression-based subclasses will have clinically important phenotypic differences. The subclass-defining expression signatures will be converted to visually intuitive "mosaics" using the Gene Expression Dynamic Inspector (GEDI) platform. After generating the subclass- defining mosaics, we will prospectively validate the ability of these mosaics to identify clinically relevant, gene expression-based septic shock subclasses using a separate cohort of 200 patients. In Specific Aim 2 we will derive a risk model for the prediction and early detection of septic shock associated renal failure (SSARF). We have objectively derived a panel of 7, serum-based, candidate protein biomarkers for the early detection of SSARF. We will measure these candidate biomarkers in a derivation cohort of 180 patients and develop a multi-biomarker based risk model. The model will be subsequently validated in a prospectively enrolled cohort of 200 patients. In Specific Aim 3 we will sequence the entire matrix metallopeptidase-8 (MMP-8) gene region and measure associations between sequence variations and illness severity. We will also test associations between MMP-8 sequence variations and expression levels of MMP-8 (mRNA, protein, and activity). The expected deliverables of this application are novel tools for clinically useful stratification of sptic shock. PUBLIC HEALTH RELEVANCE: The deliverable of this program will be a set of novel tools to more effectively stratify patients with septic shock. Child health will be positively impacted by developing the capability to more effectively stratify patients for interventional clinical trials nd for the application of high risk therapies in children with septic shock.

描述（由申请人提供）：败血性休克是成人和儿童的主要公共卫生问题。败血性休克是一种在给定患者队列中具有高度可变表达的异质综合征。该领域的一个主要挑战是通过更有效地对患者进行更有效的患者进行分层，以进行更合理有效的临床研究和个性化的临床管理，以减少和管理这种异质性。在过去的7年中，我们开发了败血性休克儿童的基因组表达数据库。现在，我们提议利用这个丰富注释的数据库来开发新的化脓性休克分层工具通过3个特定目的，重点是基于基因表达的败血性败血性休克亚类，生物标志物，用于早期检测性败血性休克相关的肾衰竭以及在症状生物学中对新型候选基因的基因分型。在特定的目标1中，我们将得出一种分类策略，该策略将基于100个基因表达特征的败血性休克患者分为不同的子类。分类策略将在现有的180名患者的队列中得出，并将使用纳米弦乐NCounter平台进行基因表达测量。基于我们最近发布的数据，我们希望基于表达的亚类具有临床上重要的表型差异。定义子类表达特征将使用基因表达动态检查器（GEDI）平台转换为视觉直观的“马赛克”。在产生亚类定义镶嵌物后，我们将前瞻性地验证这些镶嵌物使用200名患者的单独同类群体鉴定基于基因表达的败血性败血性休克亚类的能力。在特定目标2中，我们将得出一个风险模型，以预测和早期检测与败血性休克相关的肾衰竭（SSARF）。我们客观地得出了一个由7个基于血清的，候选蛋白生物标志物的面板，用于早期检测SSARF。我们将在180名患者的派生队列中衡量这些候选生物标志物，并开发基于多生物标志物的风险模型。该模型将随后在前瞻性招募的200名患者的队列中得到验证。在特定的目标3中，我们将对整个基质金属肽酶-8（MMP-8）基因区域进行测量，并测量序列变化和疾病严重程度之间的关联。我们还将测试MMP-8序列变化与MMP-8（mRNA，蛋白质和活性）的表达水平之间的关联。该应用程序的预期可交付成果是用于SPTIT休克临床有用分层的新工具。 公共卫生相关性：该计划的可交付将是一组新型工具，可以更有效地对败血性休克进行分层。儿童健康将通过开发更有效地对患者进行介入临床试验的能力进行积极影响，以在败血性休克儿童中应用高风险疗法。