Modifier genes of sepsis

败血症的修饰基因

基本信息

批准号：
7281718
负责人：
Antonio De Maio
金额：
$ 28.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7281718
关键词：
A/J Mouse Acute Adult Respiratory Distress Syndrome Age Age-Years Bioinformatics Candidate Disease Gene Caring Chromosomes Chromosomes, Human, 1-3 Chromosomes, Human, Pair 8 Code Coin Complex Condition Congenic Mice Critical Illness Endotoxemia Environment Escherichia coli Etiology Functional disorder Genes Genetic Genetic Polymorphism Goals Health Inbred Strains Mice Individual Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Interleukin-10 Interleukins Investigation Knock-out Ligation Lipopolysaccharides Maps Messenger RNA Modeling Morbidity - disease rate Mouse Strains Multiple Organ Failure Mus Numbers Organ Outcome Pathway interactions Patients Pattern Peritoneal Peritoneal Macrophages Phenotype Plasma Process Proteins Puncture procedure Quantitative Trait Loci Recombinant Inbred Strain Recombinants Regulation Reporting Respiratory distress Risk Role Secondary to Sepsis Syndrome Trauma Variant Wild Type Mouse base clinically relevant consomic cytokine genetic variant human disease macrophage macrophage scavenger receptors mortality mouse model positional cloning sex

项目摘要

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.

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一个主要健康问题。与创伤相关的死亡率和发病率部分是由于初始损伤引发的继发性疾病，例如败血症、急性呼吸窘迫和多器官功能障碍综合征。虽然这些病症的确切病因尚不清楚，但它们可能是由过度的炎症过程引起的。一些因素，包括起始损伤、环境、性别、年龄和基因组成，被认为可以调节炎症过程，从而决定临床患者的最终结果。最近在小鼠模型中表明了遗传对炎症过程的影响。注射细菌脂多糖（IPS）后，已绘制了炎症期间细胞因子血浆水平的几个数量性状位点（QTL）。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。该区域的候选基因巨噬细胞清道夫受体 1 (Msr1) 已经出现。这项研究的首要目的是确认 Msr1 在炎症过程中的作用。第二个目标是在临床上更相关的脓毒症、盲肠结扎和穿刺小鼠模型中绘制调节炎症过程的其他基因。 QTL将使用重组近交小鼠品系进行定位，并使用同体和同类小鼠进行确认。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结合来鉴定。因此，该提案的总体目标是鉴定有助于实验小鼠模型中炎症反应的基因。调节小鼠炎症程度的基因可能与影响人类疾病的基因具有相同的途径，并可能最终为识别处于严重炎症风险的个体提供基础。