慢性阻塞性肺疾病（COPD）是世界范围第四大疾病死亡原因。吸烟﹑空气污染（如高PM2.5雾霾）和某些基因的多态性是引起COPD的主要因素。表面活性蛋白D（SP-D）主要功能是宿主防卫，免疫和炎症调节及维持肺泡稳态。最近研究表明SP-D的表达和SP-D的基因型与COPD密切相关，携带SP-D C等位基因的人群比SP-D T人群对COPD更易感。其机制尚不清楚。我们假设SP-D通过调节肺免疫和炎症及信号途径来影响COPD发生，C等位基因比T有较弱的调节功能。本题旨在通过野生型﹑SP-D 基因敲除和人源化SP-D转基因小鼠的COPD模型，利用呼吸生理，肺组织病理，细胞和分子水平的多方面技术，明确SP-D在COPD病理的作用及对肺免疫和炎症信号途径的调节功能，阐明人类SP-D基因多态性导致COPD不同易感性的机制。此题将为防治COPD提供新的理论依据，为靶点药物研发提供首个人源化COPD动物模型。

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and the prevalence is predicted to increase in the coming two decades. Cigarette smoking, ambient air pollution (especially high level of PM2.5) as well as some human gene polymorphisms (alleles) are risk factors to trigger COPD. Surfactant protein D (SP-D) in the lung plays a critical role in the host defense, regulation of immunity and inflammation, and pulmonary alveolar homeostasis. Recent studies demonstrate that SP-D expression and SP-D genetic variation are significantly associated with COPD and that individuals with SP-D C allele are more susceptible to COPD incidence compared to those with SP-D T allele. However, the mechanism of SP-D function in COPD is poorly understood so far. We hypothesize that SP-D plays a critical role in the pathogenesis of COPD through modulating immunity and inflammation, as well as related signaling pathways in the lung, and that human SP-D C allele has weaker ability compared to SP-D T allele. In this study we will establish one unique COPD model with three types of mice, i.e. Wild-type C57BL/6, SP-D knockout (KO), and humanized SP-D transgenic mice, and then investigate the roles of SP-D and human SP-D alleles in the pathogenesis of COPD on its regulation of immunity and inflammation, and related signaling pathways, using multiple techniques including respiratory physiology, histology, immunohistochemistry, cellular and molecular biology. Furthermore, this proposed study will elucidate functionally different mechanisms of human SP-D alleles associated with COPD. Successful completion of the proposal will generate first COPD model with humanized SP-D transgenic mice, which can provide a powerful in vivo tool for gene/allele-specific COPD drug development and gene/allele-environment interactions. The knowledge gained from this study will provide scientific basis for COPD therapy and personalized medicine.