Modeling the role of DNA variants in the pathogenesis of lung disease

描述(由申请人提供)：遗传学研究，包括关联研究和最近的全基因组关联研究，已经确定了大量的DNA变异，这些变异可能会导致特应性疾病、哮喘和慢性阻塞性肺病的发生。然而，在大多数这些研究中，功能变体还没有被确定。这在很大程度上反映了这样一个事实，即在大多数情况下，所发现的多态(S)不会改变位于这些区域的基因编码的蛋白质的结构；相反，变异通常在非编码的dna中发现。虽然这些区域通常包括在基因表达调控中发挥重要作用的序列，包括启动子、增强子或绝缘体区域，但目前可用于评估这些DNA变异在确定特定基因在正常发育过程中的表达的重要性，以及可能更重要的是，在确定这些变异对疾病风险、疾病进展和/或患者对特定治疗干预的反应的影响方面的工具有限(S)。此外，在大多数情况下，很明显，多个基因座上的DNA变异与环境因素一起决定了疾病的风险：这些相互作用仍然特别难以定义。在本申请中，我们建议 为了检验这样一种假设，即可以建立小鼠模型来测试疾病相关的非编码DNA变体的影响。这些小鼠模型将允许测试风险相关的单倍型，并提供一种方法来解决单个DNA变异对基因表达的影响。风险相关单倍型或个体变异导致的基因调控变化的影响可以结合环境因素，也可以结合其他非连锁基因座的疾病相关DNA变异来评估。

DESCRIPTION (provided by applicant): Genetic studies, both association studies and more recently genome wide association studies (GWAS), have identified a large number of DNA variants that potentially confer risk for the development of atopy, asthma and COPD. However, in the majority of these studies the functional variant has not been identified. This largely reflets the fact that, in most cases, the polymorphism(s) identified do not alter the structure of the proteins encoded by genes located in these regions; rather the variants are generally found in non-coding DNA. While these regions often include sequences that could play an important role in regulation of gene expression, including promoters, enhancers or insulator regions, limited tools are currently available to assess the importance of these DNA variations in determining the expression of a given gene during normal development and, perhaps more importantly, in determining the impact of these variations on risk for disease, disease progression and/or the response of the patient to specific therapeutic intervention(s). Furthermore, in most cases it is clear that DNA variants at multiple loci, together with environmental factors, determine risk for disease: these interactions remain particularly difficult to define. In this application we propose to test the hypothesis that mouse models can be developed for testing the impact of disease associated non-coding DNA variants. These mouse models will allow testing of risk associated haplotypes as well as provide a means of resolving the contribution of an individual DNA variation on gene expression. The impact of the change in gene regulation conferred by the risk associated haplotype or individual variant can be evaluated in combination with environmental factors and also in combination with disease associated DNA variants at other unlinked loci.