Modifier genes of sepsis

败血症的修饰基因

基本信息

批准号：
7892196
负责人：
Antonio De Maio
金额：
$ 7.65万
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：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7892196
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 Congenic Mice Critical Illness Endotoxemia Environment Escherichia coli Etiology 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 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 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）：尽管护理重症患者的护理方面取得了巨大进展，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引发损伤（例如败血症）和急性呼吸窘迫和多个器官功能障碍综合征引起的次要条件。尽管这些疾病的确切病因尚不清楚，但它们可能是由于夸张的炎症过程而导致的。已经提出了几个因素，包括发起侮辱，环境，性别，年龄和遗传化妆，以调节炎症过程，从而确定临床患者的最终结果。最近在鼠模型中表明了对炎症过程的遗传贡献。注射细菌脂多糖（IPS）后，已经映射了几个定量性状基因座（QTL）用于炎症过程中细胞因子血浆水平的几个定量性状基因座（QTL）。特别是，发现了LPS诱导的白介素（IL）10的小鼠染色体上的QTL。该区域中的一个候选基因，巨噬细胞清除剂受体1（MSR1）已经出现。这项研究的第一个目的是确认MSR1在炎症过程中的作用。第二个目的是绘制在更临床相关的败血症，盲肠结扎和穿刺模型中调节炎症过程的其他基因。 QTL将使用重组近交小鼠菌株进行映射，并使用辅助和先天小鼠确认。这些基因座中的候选基因将通过生物信息学和位置克隆的结合来鉴定。因此，该提案的总体目的是确定在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影响人类疾病的人相同的途径，并最终可能为识别有夸张炎症状况的人提供基础。