Genomic Analysis of Pediatric SIRS

描述(由申请人提供)： 全身炎症反应综合征(SIRS)是一个临床概念，描述了宿主对各种疾病过程的一般反应。SIRS在危重儿童中的发生率非常高，大多数临床医生都经历过令人沮丧的场景，一些SIRS儿童进展为感染性休克、多器官功能障碍综合征(MODS)和死亡，尽管似乎是最佳的治疗方案。一个生物学上看似合理的解释可能在于个体宿主的遗传背景，它可以解释一些全身炎症反应综合征(SIRS)儿童感染性休克/多器官功能障碍/死亡的发生，而不是在其他儿童中。也就是说，在SIRS中，宿主遗传背景的差异可能导致异常的促炎和/或抗炎反应，从而导致感染性休克/多器官功能障碍综合征/死亡。这一建议的中心假设是基于这样一个前提，即真正了解个体宿主对SIRS的反应依赖于基因组水平的研究，并且微阵列技术提供了检验这一假设的有效手段。我们的初步数据表明，从全血中提取的RNA可以用于基因芯片分析，有效地研究SIRS和感染性休克儿童的基因组反应。这一建议的另一个前提是，宿主对SIRS的反应存在显著的发育差异，因此有理由在青春期前人群中进行这种类型的研究。因此，该建议的中心假设是，在全身炎症反应综合征的儿童中，发展为感染性休克、MODS和/或死亡的过程在很大程度上取决于一组确定的多基因产物的可发现的表达模式和相互作用。为了验证这一假设，我们将生成一个全国性的、种族多样化的、患有全身炎症反应综合征、感染性休克和/或多器官功能障碍综合征(特定目标I)的儿童的基因组数据库。该数据库将用于利用微阵列技术进行研究，旨在阐明全身炎症反应综合征、感染性休克和多器官功能障碍综合征期间宿主基因组的反应(特定目标II)。来自特定AIM II研究的数据将在蛋白质表达水平上得到部分证实(特定AIM III)。这些数据将为更全面地了解这些重要的临床问题提供基本的基础，从而可能开辟新的研究领域，从而允许开发更具体和有效的治疗干预措施。

DESCRIPTION (provided by applicant): The systemic inflammatory response syndrome (SIRS) is a clinical concept describing a generic host response to various disease processes. The incidence of SIRS is very high in critically ill children and most clinicians have experienced the disheartening scenario wherein some children with SIRS progress to septic shock, multiple organ dysfunction syndrome (MODS), and death, despite seemingly optimal treatment. One biologically plausible explanation to account for the development of septic shock/MODS/death in some children with SIRS, but not in others, may lie in the genetic background of the individual host. That is, differences in the host's genetic background can lead to a dysregulated proinflammatory and/or antiinflammatory response, in the setting of SIRS, which can subsequently lead to septic shock/MODS/death. The central hypothesis of this proposal is based on the premise that a true understanding of the individual host's response to SIRS is dependent on genome-level investigations and that microarray technology affords an effective means to test this hypothesis. Our preliminary data indicate that RNA derived from whole blood can be used for microarray analyses to effectively study the genomic response of children with SIRS and septic shock. An additional premise of this proposal is that significant developmental differences exist in the host response to SIRS to warrant this type of investigation in an exclusively pre-pubertal population. Accordingly, the central hypothesis of this proposal is that in children with SIRS, the progression to septic shock, MODS, and/or death is, in large part, dependent on the discoverable expression patterns and interactions of a defined set of multiple gene products. To test this hypothesis we will generate a national-level, ethnically diverse, genomic database of children with SIRS, septic shock, and/or MODS (Specific Aim I). This database will be used for studies designed to elucidate the host genomic response during SIRS, septic shock, and MODS using microarray technology (Specific Aim II). Data derived from Specific Aim II studies will be partially confirmed at the level of protein expression (Specific Aim III). These data will provide the fundamental foundation for a more comprehensive understanding of these important clinical problems and thereby potentially open up new areas of investigation that will allow for the development of more specific and effective therapeutic interventions.