Principal Investigator: Dr. Duo Zhang
Our group focuses on developing innovative basic and translational studies, which will expand our understanding of the genes involved in the pathogenies of pneumonia. Specifically, we are trying to address the scientific questions: how these genes are regulated and what their roles are during bacterial infection. In the long term, our group will develop novel approaches and technologies to help prevent, diagnose, and cure of patients with pneumonia.
Our ongoing work is focused on innate immunity and bacterial pneumonia:
(1) To investigate the regulation and function of long non-coding RNA in macrophages during bacterial-induced pneumonia.
Gram-negative (G-) bacteria frequently induce an overwhelming inflammatory response in hosts. Despite years of research, the regulation of the inflammatory response after G- bacterial infection remains unclear, thus impeding the development of novel therapeutic/diagnostic strategies. Mammalian genomes encode thousands of long non-coding RNAs (lncRNAs). LncRNAs are extensively expressed in various immune cells including the monocytes, and macrophages. The lncRNAs have been reported to be involved in diverse biological processes, including the regulation of the expression of genes, the dosage compensation and genomics imprinting, but as yet very less research has been carried out to explore how they alter cell differentiation/function during host-pathogens interactions. We found that Lincenc1 is strikingly induced in the lungs obtained from the mice infected with G- bacteria or after exposure to LPS, an abundant glycolipid of the outer membrane of G- bacteria. Furthermore, our in vitro data suggest that Lincenc1 is induced in macrophages but not in other cells, such as the epithelial cells and neutrophils. Functionally, Lincenc1 promotes the classical activation of macrophages and the secretion of inflammatory cytokines. Here we propose that lncRNA Lincenc1 promotes G- bacterial/LPS induced lung inflammation via activating alveolar macrophages. To test this hypothesis, we propose the following two specific aims: Specific Aim I: To investigate the role of Lincenc1 in macrophage activation in vitro. Specific Aim 2: To investigate the role of Lincenc1 in lung inflammation in vivo. Successful completion of the proposed aims will uncover the role of Lincenc1 in G- bacterial infections. This study potentially will help to identify novel mechanisms and/or therapeutic strategies for lung inflammation and injury.
(2) To investigate microRNA-mediated thyroid hormone action in macrophage maturation and activation.
Depression of thyroid function is often observed in patients in ICU, which is characterized by decreased blood total triiodothyronine (T3) and free T3. Although thyroid dysfunction seems to be associated with a worse prognosis, it is still unclear whether this alteration is a protective adaption or maladaptive response. To date, the beneficial effect of replacing thyroid hormone (TH) on outcome in ICU patients is still controversial. Macrophages play a key role in innate immunity and host defense, forming the first line of defense against bacterial infection. Currently, accumulating data show that TH can significantly affect the function of the immune system and exert responses in various immune cells, including dendritic cells, lymphocytes, and more importantly, macrophages. MicroRNAs (miRNAs) are a group of small, non-coding RNAs that negative-regulate the expression of target genes at the post-transcriptional level. Currently, accumulating data show that miRNAs are key regulators to fine-tune the expression of hundreds of target genes and involved in a range of biological processes, such as cell growth and differentiation. In this study, we propose that TH controls the immune response of macrophages through enhanced phagocytosis and mitochondrial ROS generation. For the mechanistic studies, we will focus on miR-186, which was significantly induced by T3 in macrophages. Besides the miRNAs, we plan to screen coding genes by RNA sequencing. It may provide a better understanding of the transcriptome that altered by TH in macrophages. Collectively, successful completion of the proposed studies might provide fundamental knowledge of TH action in the innate immune system.
(3) Diagnostic and Therapeutic applications of extracellular vesicles in pneumonia.
Extracellular vesicle (EV) is generated by most mammalian cells and are ubiquitous in body fluids. It is well known that EV is secreted as a cell-to-cell communication mediator in physiological and pathological scenarios. EV contains proteins and nucleic acids that are derived from the EV producing cells. These EV-containing molecules have great potentials to serve as biomarkers for the diagnostics of human diseases. Besides, EV is nanovesicle in nature with low toxic and immunogenic effects. It is an ideal candidate for targeted drug delivery. In our previous studies, we have found EV-containing miR-142 and miR-223 in the circulation could reflect bacterial-induced lung inflammation. It also suggests that EV has the potential to serve as a biomarker for pneumonia. On the other hand, our studies demonstrated that EV can be used as a vehicle to transfer small RNA, such as miRNA and siRNA, to the recipient cells. The administrated EV is selectively taken up by lung macrophages, which provides a useful tool to specifically targets the innate immune system in the lung. In our further studies, we will perform translational studies to explore the EV component as diagnostics for lung diseases. Additionally, our group will continue the investigation of EV-based targeted delivery technology.
Other Research Interests
Sepsis, Chronic Obstructive Pulmonary Disease (COPD)