Investigating the role of the R213G SOD3 polymorphism in lung disease

描述(申请人提供)：rs1799895单核苷酸多态(SNP)是SOD3中的一个非同义碱基对变化，导致细胞外超氧化物歧化酶蛋白(EC-SOD)中的精氨酸到甘氨酸替代(R213G)。这个区域负责EC-SODS与细胞外基质的结合，使血浆水平增加10倍。R213G SNP保护吸烟者免受慢性阻塞性肺疾病(COPD)和COPD急性加重的影响。这项建议的目的是阐明R213G保护肺免受烟草烟雾影响的机制。为了实现这一目标，我们创造了一个具有相同SNP的敲入鼠。我们的方法将利用十多年研究EC-SOD基因和COPD的经验。 公共卫生相关性：慢性阻塞性肺疾病(COPD)是美国第四大最常见的死亡原因。主要的危险因素是吸烟；然而，大多数吸烟者不会患上慢性阻塞性肺疾病。尽管COPD被认为是一种遗传性疾病，但只有少数几种基因变异与COPD反复相关。其中一种变异是细胞外超氧化物歧化酶基因(SOD3)的R213G单核苷酸多态，它可以保护吸烟者免受COPD和COPD恶化的影响。本研究将探讨R213G保护肺免受香烟所致肺损伤的机制。这些知识可能有助于开发新的诊断测试和治疗方法来预防和治疗COPD。

DESCRIPTION (provided by applicant): The rs1799895 single nucleotide polymorphism (SNP) is a non-synonymous base pair change in SOD3 that results in an arginine-to-glycine substitution (R213G) in extracellular superoxide dismutase protein (EC-SOD). This region is responsible for EC- SODs binding to extracellular matrix increases plasma levels 10-fold. The R213G SNP protects smokers from developing chronic obstructive pulmonary disease (COPD) and acute exacerbations of COPD. The goal of this proposal is to elucidate the mechanism by which the R213G protects the lung from tobacco smoke. To accomplish this aim, we have created a knock-in mouse with the identical SNP. Our methods will utilize more than a decade of experience studying the EC-SOD gene and COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death in the United States. The major risk factor is smoking; however, most smokers do not develop COPD. Although COPD is thought to be a genetic disease, there are only a few gene variants that have been repeatedly associated with COPD. One of these variants, the R213G single nucleotide polymorphism in the extracellular superoxide dismutase gene (SOD3), protects smokers from COPD and COPD exacerbations. This study will investigate the mechanisms by which R213G protects the lungs from cigarette-induced lung injury. This knowledge may help develop novel diagnostic tests and therapies to prevent and treat COPD.