Modifier genes of sepsis

描述(由申请人提供)：尽管在危重病人的护理方面取得了巨大的进步，但创伤仍然是美国国内的一个主要健康问题。与创伤相关的死亡率和发病率在一定程度上是由于最初的侮辱引发的继发性疾病，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，但它们很可能是夸大的炎症过程造成的。一些因素，包括最初的侮辱、环境、性别、年龄和基因组成，被认为可以调节炎症过程，从而决定临床疾病患者的最终结果。最近在小鼠模型中发现了致炎过程中的遗传因素。在注射细菌脂多糖(IPS)后，已定位了炎症过程中细胞因子血浆水平的几个数量性状基因座(QTL)。特别是，在小鼠8号染色体上发现了一个与内毒素诱导的白介素10有关的QTL。在该区域出现了一个候选基因，即巨噬细胞清道夫受体1(Msr1)。这项研究的第一个目的是确认Msr1在炎症过程中的作用。第二个目标是定位在更具临床相关性的脓毒症、盲肠结扎和穿孔小鼠模型中调节炎症过程的其他基因。QTL将使用重组近交系小鼠品系进行定位，并使用同系小鼠和同系小鼠进行确认。这些基因座中的候选基因将通过生物信息学和位置克隆相结合的方法来识别。因此，这项建议的总体目标是在实验小鼠模型中识别与炎症反应有关的基因。控制小鼠炎症程度的基因很可能与那些影响人类疾病的基因存在相同的途径，并最终可能为识别处于夸大炎症条件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.