Modifier genes of sepsis

描述（由申请人提供）：尽管在重症患者的护理方面取得了巨大进步，但创伤仍然是美国的主要健康问题。与创伤相关的死亡率和发病率部分是由于由初始损伤引发的继发性疾病，如败血症、急性呼吸窘迫和多器官功能障碍综合征。虽然这些疾病的确切病因尚不清楚，但它们可能是由夸大的炎症过程引起的。已经提出了几个因素，包括初始损伤、环境、性别、年龄和遗传组成，来调节炎症过程，从而决定临床疾病患者的最终结果。最近在小鼠模型中表明了对炎症过程的遗传贡献。在注射细菌脂多糖（IPS）后，炎症期间细胞因子血浆水平的几个数量性状位点（QTL）已被定位。特别是，在小鼠8号染色体上发现了LPS诱导的白细胞介素（IL）10的QTL。在这个区域的候选基因，巨噬细胞清道夫受体1（Msr1），已经出现。本研究的第一个目的是确认Msr1在炎症过程中的作用。第二个目的是针对映射额外的基因，调节炎症过程中的一个更临床相关的小鼠模型败血症，盲肠结扎和穿孔。QTL将使用重组近交系小鼠品系进行定位，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，该提案的总体目标是确定实验小鼠模型中有助于炎症反应的基因。调节小鼠炎症程度的基因可能与那些影响人类疾病的基因沿着相同的途径，并可能最终为识别处于夸大炎症状况风险中的个体提供基础。

DESCRIPTION (provided by applicant): 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.