Study the Pathophysiological Role of Microrna in the Development of Emphysema(3/3)

Emphysema, characterizing as excess inflammation and abnormal protease/ anti-protease imbalance-mediated destruction of the lung parenchyma, is a result of chronic obstructive pulmonary disease (COPD). COPD is one of the leading causes of mortality and morbidity worldwide and effective therapies are imperfect, hence an urgent need for new therapeutic alternatives. Despite being the main risk factor, only about 20% of cigarette smokers develop emphysema. Therefore, there may be unidentified genes which predispose to smoking-induced emphysema. The susceptibility of emphysema can occur through the reduction in histone deacetylase 2 (HDAC2) or the overexpression of prothymosin α (ProT). Nevertheless, the molecular mechanisms especially in post-transcription underlying the imbalanced regulation of HDAC and ProT are largely unknown. MicroRNAs (miRNA), which function in RNA silencing and post-transcriptional regulation of gene expression, have been reported that some of their abnormal expressions in the pathogenesis of emphysema. However, the target genes of these emphysematous-associated miRNAs still need to be identified. This project is designed to study the mechanisms whether different miRNAs expression will control HDAC2 reduction or ProT overexpression in emphysema development. We preliminarily identified the aberrant expression of miR-223, miR-1, and miR-34a, according to the recent reports and microarray data, or miRBase database, may be possibly correlated with that of HDAC2 and ProT in emphysema. In this project we will in vivo analysis lung species of human emphysema from COPD patients and mouse emphysema, and in vitro confirm the detailed mechanisms regarding the up-down-stream correlation of miR-223, miR-1, miR-34a, HDAC2, and ProT. Gene therapy of lentiviral vector encoding locked nucleic acid of miR-223 (miR-223 LNA, the miR-223T) or miR-1 will be designed as the therapeutic strategy for cigarette smoke-induced emphysema model of mice. Taken together, we anticipate the success of this project will extend our understanding of the molecular mechanisms underlying the abnormal regulation of miRNAs especially miR-223 and miR-1, which may be important for predisposing individual to smoking-induced emphysema. Furthermore, we propose to provide the new direction for future therapeutic strategies to emphysema.