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（GWAS），已经确定了大量可能导致特应性、哮喘和COPD发展风险的DNA变异。然而，在大多数这些研究中，功能变异尚未被确定。这在很大程度上反映了这样一个事实，即在大多数情况下，鉴定出的多态性不会改变位于这些区域的基因编码的蛋白质的结构；相反，这些变异通常存在于非编码DNA中。虽然这些区域通常包括可能在基因表达调控中发挥重要作用的序列，包括启动子、增强子或绝缘子区域，但目前可用的工具有限，无法评估这些DNA变异在确定正常发育期间特定基因表达方面的重要性，或许更重要的是，无法确定这些变异对疾病风险的影响。疾病进展和/或患者对特定治疗干预的反应。此外，在大多数情况下，很明显，多个位点的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确定。在这个应用程序中，我们提出

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.