Modifier genes of sepsis

尽管在危重病人的护理方面取得了巨大的进步，但创伤仍然是一个主要的健康问题 在美国境内。与创伤相关的死亡率和发病率部分是由于继发性疾病 由初始损伤（如脓毒症）和急性呼吸窘迫和多器官功能衰竭引发 功能障碍综合征虽然这些疾病的确切病因尚不清楚，但它们可能是由 一种夸张的炎症过程几个因素，包括发起侮辱，环境，性别，年龄， 基因组成，已经提出来调节炎症过程，因此，决定了最终的 临床病人的结局。最近发现， 在小鼠模型中显示。几个数量性状基因座（QTL）的细胞因子血浆水平， 已经在注射细菌脂多糖（IPS）后绘制了炎症。特别是， 小鼠染色体8发现了LPS诱导的白细胞介素（IL）10。在这个区域的候选基因， 巨噬细胞清道夫受体1（Msr1）。本次调查的第一个目的是确认 Msr1在炎症中的作用第二个目标是定位调节细胞凋亡的其他基因。 在更临床相关的脓毒症、盲肠结扎和穿孔的鼠模型中观察炎症过程。QTL 将使用重组近交系小鼠品系进行作图，并使用同源和同源小鼠进行确认。 这些基因座内的候选基因将通过生物信息学和定位克隆的组合来鉴定。 因此，本提案的总体目标是确定有助于炎症反应的基因 在实验小鼠模型中。调节小鼠炎症程度的基因可能沿着 与影响人类疾病的途径相同，并可能最终为识别 处于夸大的炎症状况的风险中的个体。

Despite tremendous advances in the care of critically ill patients, trauma remains a major health problem within the US. Mortality and morbidity associated with trauma are due in part to secondary conditions triggered by the initiating insults, such as sepsis, and acute respiratory distress and multiple organ dysfunction syndromes. While the precise etiologies of these conditions are unknown, they likely result from an exaggerated inflammatory process. Several factors, including initiating insult, environment, sex, age, and genetic make up, have been proposed to regulate the inflammatory process, thus, determining the final outcome of clinically ill patients. A genetic contribution to the inflammatory process has recently been indicated in murine models. Several quantitative trait loci (QTL) for cytokine plasma levels during inflammation have been mapped after injection of bacterial lipopolysaccharide (IPS). In particular, a QTL on mouse Chromosome 8 was found for LPS-induced interleukin (IL) 10. A candidate gene in this region, macrophage scavenger receptor 1 (Msr1), has emerged. The first aim of this investigation is to confirm the role of Msr1 during inflammation. The second aim is directed at mapping additional genes that regulate the inflammatory process in a more clinically relevant murine model of sepsis, cecal ligation and puncture. QTL will be mapped using recombinant inbred mouse strains and confirmed using consomic and congenic mice. Candidate genes within these loci will be identified by a combination of bioinformatics and positional cloning. Thus, the overall objective of this proposal is to identify genes that contribute to the inflammatory responses in experimental mouse models. Genes regulating the degree of inflammation in mice are likely to lie along the same pathways as those influencing human disease and may ultimately provide a basis for identifying individuals at risk for exaggerated inflammatory conditions.