Stratification of pediatric septic shock

描述（由申请人提供）：感染性休克是成人和儿童的主要公共卫生问题。脓毒性休克是一种异质性综合征，在给定的患者队列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，以实现更合理有效的临床研究和个性化临床管理。在过去的7年里，我们已经开发了一个感染性休克儿童的基因组表达数据库。我们现在建议利用这个注释丰富的数据库，通过3个特定目标开发新的脓毒性休克分层工具，重点关注基于基因表达的脓毒性休克亚类，早期检测脓毒性休克相关肾衰竭的生物标志物，以及脓毒症生物学中新候选基因的基因分型。在具体目标1中，我们将推导出一种分类策略，该策略基于100个基因表达特征将感染性休克患者分组为不同的亚类。将在现有的180例患者队列中推导分类策略，并使用NanoString nCounter平台进行基因表达测量。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重要的表型差异。使用基因表达动态检查器（GEDI）平台，将子类定义表达签名转换为视觉直观的“马赛克”。在生成亚类定义的镶嵌图后，我们将使用200名患者的单独队列前瞻性地验证这些镶嵌图鉴定临床相关的、基于基因表达的脓毒性休克亚类的能力。在具体目标2中，我们将推导出一个预测和早期检测脓毒性休克相关性肾衰竭（SSARF）的风险模型。我们已经客观地推导出一组7个基于血清的候选蛋白质生物标志物，用于早期检测SSARF。我们将在180例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例患者的前瞻性入组队列中进行验证。在特定目标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序列变异与MMP-8表达水平（mRNA、蛋白质和活性）之间的关联。该应用程序的预期可交付成果是用于临床上有用的休克分层的新型工具。 公共卫生相关性：该计划的交付成果将是一套新的工具，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分层以进行干预性临床试验和在感染性休克儿童中应用高风险治疗的能力，将对儿童健康产生积极影响。

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.