Cellular metabolism in lung injury, repair and fibrosis
Idiopathic pulmonary fibrosis (IPF) is a clinically intractable disease with a life expectancy of 2-6 years post-diagnosis. Despite extensive research spanning decades, the available treatments for IPF remain disappointingly scarce. There is an urgent need to develop new therapeutic strategies rooted in a deeper understanding of the disease’s pathogenesis. The program builds upon our previous work and vision, which posits that lung fibrosis is characterized by alterations in distinct core metabolic programs across different types of pulmonary cells. This is a potentially paradigm-shifting concept that has only recently started to gain recognition. Understanding how core metabolic pathways are specifically regulated, particularly at the epigenetic level by specific miRNAs, in various pulmonary cell types, how they contribute to the pro-fibrotic phenotypic changes in the affected cells, and how metabolic intermediaries participate in intercellular communication to promote pulmonary cell dysfunction, will greatly enhance our understanding of lung fibrosis pathogenesis. In this program, we will employ genetic, epigenetic, and pharmacological approaches to fine-tune the dysregulated core metabolic program in the lungs. This will provide novel insights into the role of core metabolic abnormalities in lung fibrosis pathogenesis and help determine the optimal strategies to correct these metabolic aberrations for disease treatment.
Regulation of innate immunity and inflammasome activation in lung injury
The NLRP3 inflammasome is unique because it requires a two-step activation process: priming and activating. The priming step involves the induction of NLRP3 and pro-IL-1β, while the activating step results in full inflammasome activation triggered by an NLRP3 activator. Although the mechanism leading to NLRP3 inflammasome activation is becoming increasingly clear, the regulation of this process remains poorly defined. Dysregulation of the NLRP3 inflammasome has frequently been implicated in acute lung injury (ALI) caused by bacterial pneumonia. MafB is a member of the large MAF transcription factor subfamily and has been implicated in immune disorders, primarily concerning its role in macrophage apoptosis, phagocytosis, and the complement system. In our preliminary studies, we made an unexpected discovery that reveals a novel function of MafB in regulating NLRP3 inflammasome activation. Our findings suggest that MafB is a new negative regulator of the NLRP3 inflammasome both in vitro and in vivo. We hypothesize that LPS and P. aeruginosa-induced MafB downregulation is a crucial step for NLRP3 inflammasome priming; MafB is a key player that regulates NLRP3 inflammasome activation; MafB plays an important role in the pathogenesis of ALI; and targeting MafB is an effective therapeutic strategy for ALI. We aim to comprehensively delineate the regulation of MafB expression at the transcriptional and post-translational levels during NLRP3 inflammasome priming; to delineate the mechanism by which MafB inhibits NLRP3 inflammasome activation; and to determine the role of MafB in LPS and P. aeruginosa-induced acute lung injury (ALI).
