Search for Candidate Genes in Lung Injury

寻找肺损伤的候选基因

• 批准号: 6938297
• 负责人: Stephanie A Nonas
• 金额: $ 5.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938297
• 关键词: adult respiratory distress syndrome; disease /disorder model; gene expression profiling; gene mutation; genetic mapping; genetic susceptibility; inbreeding; laboratory rat; lipopolysaccharides; lung injury; microarray technology; postdoctoral investigator; quantitative trait loci

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.

描述（由申请人提供）：急性肺损伤（ALI）是 ICU 发病和死亡的一个重要原因。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各不相同，且相关机制仍不清楚。我们假设存在 ALI 易感性的遗传倾向。使用气管内脂多糖和机械通气模型，我们建议使用体体大鼠品系（基因组中替换有单个外源染色体的高度近交品系）进行研究，首先鉴定染色体，然后鉴定控制 ALI 反应的基因。在特定目标 #1 中，我们将描述群体亲代菌株对 LPS 和机械通气的反应，并确定菌株对 ALL 的特异性易感性。在特定目标 #2 中，我们将使用群体回交来鉴定 ALI 的染色体和数量性状位点 (QTL)。在具体目标 #3 中，我们将使用 affymetrix cDNA 微阵列进行基因表达谱分析，以鉴定与 ALI 相关的 QTL 区域内的特定候选基因。这些研究将定义对 ALI 的基因组反应，并可能发现新的靶点，从而为急性肺损伤制定新的治疗策略。