Research Projects
Our research programs focus on the understanding of the pathogenesis of respiratory and infectious diseases and the development of diagnostic tools and therapeutics for them. These diseases include non-infectious diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary diseases (COPD), and infectious diseases such as influenza, COVID-19 and tuberculosis.
Host-pathogen interactions during respiratory Infection
Respiratory viral infection: Respiratory infections impose some of the most prevalent disease burdens worldwide and are recognized as a public health priority. Influenza virus causes annual epidemics and periodic pandemics, resulting in millions of deaths. The ongoing pandemic of coronavirus disease 2019 (COVID-19) has caused hundreds of million infections and several million deaths worldwide. Due to the high mutation rate of these viruses, widespread resistance to anti-viral drugs targeting viral proteins constitutes a major challenge for therapeutic intervention. Because all viruses utilize host factors and machinery to complete their life cycle, targeting host factors that regulate virus replication may provide a solution to mutagenesis-associated viral escape. Our research goal is to understand the molecular mechanisms of host factors that regulate influenza virus and SARS-CoV-2 replication and thus develop anti-viral drugs targeting these host factors.
Our first area of interest in respiratory viral infection is non-coding RNAs including microRNAs, circular RNAs and long non-coding RNAs (lncRNAs). MicroRNAs and lncRNAs have a size of ~21-23 and >200 nucleotides, respectively and have been increasingly recognized for their importance in regulating various biological processes and diseases. MicroRNAs mainly control the expression of the majority of genes at the post-transcriptional level while lncRNAs function by interacting with RNA, DNA and protein to activate or repress gene expression at various levels, including transcription, splicing, mRNA stability, and translation. Our approaches include target gene identification by expression library screening, genome-wide CRISPR library screening, and transcriptome analysis in combination with computational approaches, followed by gain-of-function and loss-of-function, mechanistic, and animal studies.
Our second area of interest in respiratory viral infection is to identify critical components in cellular signaling pathways as potential targets for developing small molecules as anti-viral agents. Once a lead compound is identified, mechanisms of action, efficacy in various animal models, toxicity and safety, and pharmacokinetics are investigated with a goal of IND filing.
Respiratory bacterial infection: There are nearly 10 million active tuberculosis patients, resulting in 1.4 million deaths annually. In collaboration with Dr. Yong Cheng in the Department of Biochemistry and Molecular Biology, OSU, we are interested in identifying anti-lncRNAs against Mycobacterium tuberculosis infection using a genome-wide CRISPR activation screen and developing lncRNAs as host-directed therapies for tuberculosis.
Pathogenesis of pulmonary diseases
Our research projects in this topic involve several lung diseases: Acute Respiratory Distress Syndrome (ARDS)/Acute Lung injury (ALI), Idiopathic Pulmonary Fibrosis (IPF), Chronic Obstructive Pulmonary Disease (COPD) and Bronchopulmonary Dysplasia (BPD). One of our current focuses is IPF. IPF is a chronic interstitial fibrotic lung disease and affects 200,000 Americans per year with a median survival of 3-5 years from diagnosis. Lung tissue scarring (fibrosis) causes incompetent oxygen transmission to the blood and organ, and commonly, respiratory failure. The disease typically occurs in adults 50 and 70 years old. Two drugs recently approved by the FDA—pirfenidone and nintedanib—reduce the lung function decline and slow the progression, but do not cure the disease. There are no curative IPF treatments. The pathological hallmark of IPF is the formation of fibroblastic foci consisting of a large number of activated and proliferated fibroblasts (myofibroblasts). These cells deposit excessive extracellular matrix, resulting in pulmonary fibrosis. Residential fibroblast proliferation and activation is thought to be one of the major contributors to the pathogenesis of IPF. Our research projects focus on the following general areas: 1) microRNA, circular RNA and long non-coding RNA regulation of cellular signaling in lung fibroblasts, 2) iron contribution to IPF, 3) ferroptosis of epithelial cells, and 4) M1/M2 macrophages in IPF.
Stem Cell Therapy and Tissue Engineering
Stem Cell Therapy: There is an increasing interest in stem cell-based therapy and tissue engineering. Several types of stem cells could be used for this purpose including embryonic stem cells (ESCs), bone-marrow-derived mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs). Stem cell therapy has the potential to repair or regenerate damaged lung tissue, presenting a promising approach for curing lung diseases. Our first area of interest in the stem cell field is to engineer MSCs and iPSCs for better therapies of lung diseases. Epithelial cell damage is a common feature in many pulmonary diseases such as IPF, COPD, ARDS and influenza or bacterial pneumonia. Our engineering goal is two-fold: 1) to enhance alveolar epithelial repair by promoting the differentiation of MSCs or iPSCs to alveolar epithelial cells or by stimulating endogenous local stem cells to regenerate lung epithelial cells, and 2) reversing pathological processes such as fibrosis, inflammation, and viral or bacterial replication via exosome-mediated transfer of molecules from stem cells to lung cells or alteration of stem cell secretome.
Tissue Engineering: Our second area of interest in stem cell is to build human lung tissue models for translation research with a ultimate goal of generating a bioartificial lung for organ transplant. Due to a lack of human lung tissue models, most current investigations in the field use 2D cell culture and mouse models, creating a significant obstacle for translational research and resulting in clinical trial failures of many drug candidates identified in cell and rodent models. We are interested in developing renewable, readily available, patient-specific normal and diseased 3D human lung tissue-engineered models using iPSCs/MSCs-derived lung cells. These models can be used for mechanistic and translational research, for testing safety and efficacy, and for the high-throughput screening of drug candidates.