Stratification of pediatric septic shock

小儿感染性休克的分层

基本信息

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
项目类别：
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

项目摘要

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）：感染性休克是成人和儿童的一个主要公共卫生问题。感染性休克是一种异质性综合征，在给定的患者群体中具有高度可变的表达。该领域的一个关键挑战是通过更有效地对患者进行分层来减少和管理这种异质性，以实现更合理、更有效的临床研究和个体化临床管理。在过去的 7 年里，我们开发了感染性休克儿童的基因组表达数据库。我们现在提议利用这个注释丰富的数据库，通过 3 个具体目标来开发新型感染性休克分层工具，这些目标侧重于基于基因表达的感染性休克亚类、早期检测感染性休克相关肾衰竭的生物标志物，以及新型候选基因的基因分型。脓毒症生物学。在具体目标 1 中，我们将得出一种分类策略，根据 100 个基因表达特征将感染性休克患者分为不同的亚类。分类策略将在现有的 180 名患者队列中得出，基因表达测量将使用 NanoString nCounter 平台进行。根据我们最近发表的数据，我们预计基于表达的亚类将具有临床上重要的表型差异。使用基因表达动态检查器 (GEDI) 平台，子类定义的表达签名将转换为视觉上直观的“马赛克”。生成亚类定义马赛克后，我们将使用 200 名患者组成的单独队列前瞻性地验证这些马赛克识别临床相关的、基于基因表达的感染性休克亚类的能力。在具体目标 2 中，我们将推导出一个用于预测和早期检测败血性休克相关肾衰竭 (SSARF) 的风险模型。我们客观地得出了一组 7 个基于血清的候选蛋白质生物标志物，用于 SSARF 的早期检测。我们将在 180 名患者的衍生队列中测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。该模型随后将在 200 名患者的前瞻性队列中进行验证。在具体目标 3 中，我们将对整个基质金属肽酶 8 (MMP-8) 基因区域进行测序，并测量序列变异与疾病严重程度之间的关联。我们还将测试 MMP-8 序列变异和 MMP-8 表达水平（mRNA、蛋白质和活性）之间的关联。该应用的预期成果是用于临床上有用的痉挛性休克分层的新颖工具。公共卫生相关性：该计划的成果将是一套新工具，可以更有效地对感染性休克患者进行分层。通过开发更有效地对患者进行干预临床试验和对败血性休克儿童应用高风险疗法的能力，将对儿童健康产生积极影响。