Genomic analysis of pediatric SIRS and septic shock

描述（由申请人提供）：儿童感染性休克仍然是美国的一个主要公共卫生问题。全身性炎症反应综合征（SIRS）与感染性休克有生物学联系，反映了许多危重儿童普遍存在的炎症状态。我们正在研究这个临床问题，建立一个国家级SIRS和感染性休克儿童基因组数据库，并通过应用微阵列技术进行全基因组扫描。在过去的2.5年中，我们发现：a) SIRS或感染性休克的危重儿童存在临床不同的亚组，具有不同的基因表达谱；B)这些患者亚群中存在主要的相关基因网络；C)这些网络在患者亚组之间的差异表达；D)儿童感染性休克不良结局（死亡）的潜在生物标志物；e)存在一个主要的基因网络，在儿童感染性休克的非幸存者中大部分表达不足。这些发现导致了新的假设，这些假设目前正在被带回实验室和床边进行验证。我们现在寻求在这个项目成功的基础上继续建立数据库并进行进一步的基于微阵列的实验。当我们寻求继续使用更大的数据集进行面向发现的数据挖掘时，该计划的主要重点现在将是解决几个预期设计的问题。在具体目标1中，我们将通过应用生物信息学方法，利用训练数据集和验证数据集，检验SIRS和感染性休克患者亚组存在的假设。在Specific Aim 2中，我们将检验发育（以特定年龄范围内的儿童群体为模型）和病原体相关因素强烈影响SIRS和感染性休克儿童基因组水平表达谱的假设。在Specific Aim 3中，我们将验证一个假设，即通过分析来自特定白细胞亚群的RNA，可以更准确地定义SIRS和感染性休克儿童的基因组水平表达谱。通过该项目产生的数据将大大提高我们对SIRS和感染性休克的基因组水平的理解，并为新的假设、诊断方法和治疗提供基础。

DESCRIPTION (provided by applicant): Pediatric septic shock continues to be a major public health problem in the United States. The systemic inflammatory response syndrome (SIRS) is biologically linked to septic shock and reflects a generic inflammatory state present in many critically ill children. We are studying this clincial problem by establishing a national-level genomic data bank of children with SIRS and septic shock, and conducting of genome-wide scans through the application of microarray technology. Over the last 2.5 years we have found: a) the existence of clinically distinct subgroups of critically ill children with SIRS or septic shock having distinct gene expression profiles; b) the existence of major relevant gene networks within these subgroups of patients; c) differential expression of these networks between the patient subgroups; d) potential biomarkers for poor outcome (death) in pediatric septic shock; and e) the existence of one major gene network that is largely under expressed in non-survivors of pediatric septic shock. These findings have led to new hypotheses that are currently being taken back to the laboratory and bedside for validation. We now seek to build on the success of this program by continuing to build the data bank and conducting further microarray-based experiments. While we seek to continue discovery-oriented data mining with a larger data set, the main focus of the program will now be to address several prospectively designed questions. In Specific Aim 1 we will test the hypothesis that subgroups of patients with SIRS and septic shock exist by applying bioinformatic approaches that make use of a trainining data set and a validation data set. In Specific Aim 2 we will test the hypothesis that development (modeled by groups of children within specific age ranges) and pathogen- associated factors strongly influence the genome level expression profiles of children with SIRS and septic shock. In Specific Aim 3 we will test the hypothesis that the genome-level expression profiles of children with SIRS and septic shock can be more accurately defined by analyzing RNA from specific white blood cell subpopulations. The data generated through this program will serve to substantially enhance our genome level understaning of SIRS and septic shock and provide the foundation for novel hypotheses, diagnostic approaches, and therapies.