Search for Candidate Genes in Lung Injury

描述(由申请人提供)：急性肺损伤(ALI)是ICU发病率和死亡率的重要原因。肺部炎症和血管通透性增加是ALI的主要特征，但不同人群对肺损伤的反应不同，涉及的机制尚不清楚。我们假设存在易患ALI的遗传易感性。利用气管内内毒素和机械通气的模型，我们建议使用共生大鼠品系进行研究，这些品系是高度近交的品系，其基因组中含有单个外源染色体，首先识别染色体，然后识别控制ALI反应的基因。在特定的目标#1中，我们将在特定的目标#2中，我们将利用共体回交来鉴定ALI的染色体和数量性状基因座(QTL)，以确定ALI亲本菌株对LPS和机械通气的反应，并确定ALL的品系特异性易感性。在具体目标3中，我们将使用Affymetrix基因芯片进行基因表达谱分析，以寻找与ALI相关的QTL区域(S)内的特定候选基因。这些研究将确定基因组对ALI的反应，并可能发现新的靶点，可能导致新的治疗策略的急性肺损伤。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a significant cause of morbidity and mortality in the ICU. Pulmonary inflammation and increased vascular permeability are cardinal features of ALI, however the response to lung injury varies within the population and the mechanisms involved remain unclear. We hypothesize that there is a genetic predisposition for susceptibility to ALI. Using a model of intratracheal LPS and mechanical ventilation, we propose studies using consomic rat strains, highly inbred strains that have a single exogenous chromosome substituted into their genome, to identify first the chromosomes and then the genes that govern the ALI response. In Specific Aim #1, we will characterize the response to LPS and mechanical ventilation in the consomic parental strainis and determine strain-specific susceptibility to ALL In Specific Aim #2, we will use consomic backcrosses to identify the chromosomes and quantitative trait loci (QTL) for ALI. In Specific Aim #3, we wll use affymetrix cDNA microarrays to perform gene expression profiling to identify specific candidate genes within QTL region(s) involved in ALI. These studies will define the genomic response to ALI and may uncover novel targets which may lead to new therapeutic strategies in acute lung injury.