Genetic analysis of hyperoxia-induced acute lung injury

高氧所致急性肺损伤的基因分析

• 批准号: 6835127
• 负责人: Daniel R Prows
• 金额: $ 37.25万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6835127
• 关键词: adult respiratory distress syndrome; animal breeding; disease /disorder model; gene expression; gene expression profiling; genetic strain; genomic imprinting; hyperoxia; inbreeding; laboratory mouse; microarray technology; phenotype; polymerase chain reaction; quantitative trait loci; sex linked trait

DESCRIPTION (provided by applicant): Acute lung injury, including the most severe form - acute respiratory distress syndrome (ARDS), is a devastating and, too often-times, lethal condition that can result from numerous seemingly unrelated direct or indirect pulmonary insults. Hundreds of proteins associated with the initiation or progression of the disease have been tested to delineate their possible role(s); however, little progress has been made to identify the key players responsible for its morbidity and mortality. Because mortality rates have changed little over the last decade using this candidate-gene approach, alternative strategies are essential to advance our understanding of the pathobiology of acute lung injury development and progression. The goal of this research is to use mouse models of acute lung injury to identify the major quantitative trait loci (QTLs) linked to mortality. To gain preliminary data for this proposal 18 common inbred mouse strains were screened for survival time in hyperoxia (>95% O2), a prototypic agent used to induce acute lung injury and ARDS. Two mouse models of differential survival time were identified. First, C57BL/6J (B) mice are sensitive, whereas 129X1/SvJ (S) mice are much more resistant to hyperoxia-induced acute lung injury mortality. Second, the resistant S strain was combined with 129P3/J (P), a closely related, but sensitive sub strain of the 129 line. Initial results with offspring generated for each mouse model suggested a complex mode of trait inheritance, including multiple genes and other genetic and epigenetic factor(s) (e.g., decreased penetrance, parental imprinting, and and/ or mitochondrial inheritance). S and P-derived crosses also suggested sex linkage. From these preliminary data, we hypothesize that hyperoxia-induced acute lung injury survival is a quantitative trait that is amenable to genetic analysis using inbred strains of mice to model the human disease. For each mouse model, the following three specific aims are proposed: (1) determine the likely mode of overall trait inheritance (segregation analysis) and estimate the number of loci contributing to the response; (2) identify genetic regions linked to hyperoxia-induced acute lung injury survival in backcross and F2 mice (QTL analysis) generated from strains of each model; and (3) identify candidate and positional candidate genes associated with the strain survival differences (microarray analysis). With this combined approach, we expect to gain insight into not only the pathology of hyperoxia-induced acute lung injury, but also the possible similarities to other oxidant-induced acute lung injuries. The proposed studies offer a different perspective to a retractable problem and could yield valuable information urgently needed to further assess genetic differences underlying disease risks and therapeutic outcomes in the population.

描述（由申请人提供）：急性肺损伤，包括最严重的形式 - 急性呼吸窘迫综合征（ARDS），是一种毁灭性的且经常是由于许多看似无关的直接或间接肺侮辱而导致的致命状况。 已经测试了与该疾病的启动或进展相关的数百种蛋白质，以描述其可能的作用；但是，几乎没有取得进展来确定负责其发病率和死亡率的关键参与者。 由于在过去的十年中使用这种候选基因方法发生了变化，因此替代策略对于促进我们对急性肺损伤发展和进展的病理生物学的理解至关重要。 这项研究的目的是使用急性肺损伤的小鼠模型来确定与死亡率相关的主要定量性状基因座（QTL）。 为了获得该建议的初步数据，筛选了18个常见的近交小鼠菌株的生存时间（> 95％O2），这是一种用于诱导急性肺损伤和ARDS的原型剂。 确定了两个差异生存时间的小鼠模型。 首先，C57BL/6J（B）小鼠敏感，而129x1/SVJ（S）小鼠对高氧诱导的急性肺损伤死亡率具有更大的抗性。 其次，将抗性S菌株与129p3/j（p）组合，这是129条线的紧密相关但敏感的子菌株。 为每个小鼠模型产生的后代的初始结果提出了一种复杂的性状遗传模式，包括多个基因以及其他遗传和表观遗传因子（例如，渗透率降低，父母印记以及和/或线粒体遗传）。 S和P衍生的十字架还提出了性别联系。 从这些初步数据中，我们假设高氧诱导的急性肺损伤存活是一种定量性状，使用小鼠的近交菌株对遗传分析进行定量特征，以模拟人类疾病。 对于每个小鼠模型，提出了以下三个特定目标：（1）确定总体性状遗传的可能模式（隔离分析），并估计有助于响应的基因座的数量； （2）确定与高氧诱导的急性肺损伤生存有关的遗传区域（QTL分析），每种模型的菌株产生。 （3）确定与应变存活差异相关的候选和位置候选基因（微阵列分析）。通过这种联合方法，我们希望不仅可以深入了解高氧诱导的急性肺损伤的病理，而且还可以与其他氧化剂诱导的急性肺损伤有可能的相似之处。 拟议的研究为一个可伸缩的问题提供了不同的观点，并可能迫切需要提供有价值的信息，以进一步评估人群中疾病风险和治疗结果的遗传差异。