Genetic analysis of hyperoxia-induced acute lung injury

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，往往是致命的疾病，可能由许多看似无关的直接或间接肺损伤引起。 已经测试了数百种与疾病的开始或进展相关的蛋白质，以描述其可能的作用;然而，在确定其发病率和死亡率的关键因素方面几乎没有取得进展。 由于死亡率在过去十年中使用这种候选基因方法几乎没有变化，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。 本研究的目的是利用小鼠急性肺损伤模型，以确定与死亡率相关的主要数量性状基因座（QTL）。 为了获得这一建议的初步数据，筛选了18个常见的近交系小鼠品系在高氧（> 95%O2）中的存活时间，高氧是一种用于诱导急性肺损伤和ARDS的原型试剂。 确定了两种不同存活时间的小鼠模型。 首先，C57 BL/6 J（B）小鼠对高氧诱导的急性肺损伤死亡率敏感，而129 X1/SvJ（S）小鼠对高氧诱导的急性肺损伤死亡率更具抵抗力。 第二，抗性S品系与129系的密切相关但敏感的亚系129 P3/J（P）组合。 每个小鼠模型产生后代的初步结果表明了复杂的性状遗传模式，包括多个基因和其他遗传和表观遗传因素（例如，降低的遗传率、亲本印记和/或线粒体遗传）。 S和P衍生的杂交也表明性连锁。 从这些初步的数据，我们假设，高氧诱导的急性肺损伤的生存是一个数量性状，这是服从遗传分析使用近交系小鼠模型的人类疾病。 对于每种小鼠模型，提出了以下三个具体目标：（1）确定总体性状遗传的可能模式（分离分析）并估计有助于应答的基因座数量;（2）在回交和F2小鼠中鉴定与高氧诱导的急性肺损伤存活相关的遗传区域（3）鉴定与菌株存活差异相关的候选基因和位置候选基因（微阵列分析）。通过这种结合的方法，我们期望不仅深入了解高氧诱导的急性肺损伤的病理学，而且还了解与其他氧化剂诱导的急性肺损伤的可能相似性。 拟议的研究为可伸缩问题提供了不同的视角，并可能产生迫切需要的有价值的信息，以进一步评估人群中潜在疾病风险和治疗结果的遗传差异。

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.