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，描述了一个通用的主机响应各种疾病的过程。SIRS在危重患儿中的发生率非常高，大多数临床医生都经历过令人沮丧的情况，其中一些患有SIRS的儿童进展为脓毒性休克、多器官功能障碍综合征（MODS）和死亡，尽管似乎进行了最佳治疗。一个生物学上合理的解释，以解释感染性休克/MODS/死亡的发展，在一些儿童SIRS，但不是在其他人，可能在于个人主机的遗传背景。也就是说，在SIRS的情况下，宿主遗传背景的差异可导致失调的促炎和/或炎症反应，其随后可导致败血性休克/MODS/死亡。该建议的中心假设是基于这样的前提，即真正了解个体宿主对SIRS的反应依赖于基因组水平的调查，并且微阵列技术提供了一种有效的手段来测试这一假设。我们的初步数据表明，来自全血的RNA可用于微阵列分析，以有效地研究SIRS和感染性休克儿童的基因组反应。该提议的另一个前提是，宿主对SIRS的反应存在显著的发育差异，以保证在完全青春期前人群中进行此类研究。因此，该提案的中心假设是，在患有SIRS的儿童中，脓毒性休克、MODS和/或死亡的进展在很大程度上取决于可发现的表达模式和一组确定的多个基因产物的相互作用。为了验证这一假设，我们将建立一个国家级的、种族多样的、患有SIRS、脓毒性休克和/或MODS（特定目标I）的儿童基因组数据库。该数据库将用于设计用于使用微阵列技术阐明SIRS、败血性休克和MODS期间宿主基因组反应的研究（Specific Aim II）。将在蛋白质表达水平（特异性目的III）部分确认特异性目的II研究的数据。这些数据将为更全面地了解这些重要的临床问题提供基础，从而可能开辟新的研究领域，从而开发出更具体、更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.