1. Host and Environment interaction with respect to lung epithelial cell phenotype, differentiation, and function.
My laboratory provided influential identification and characterization of a novel lung epithelial cell-specific, secretory protein SPLUNC1 (BPIFA1) and its crucial roles in pulmonary diseases. Two consecutive R01 grants have supported the SPLUNC1-associated research since 2008, including the ongoing clinical, ancillary study investigating its association with exacerbation in severe asthma. We and others have demonstrated multiple functions of SPLUNC1, including host defense, anti-inflammatory effects, a surfactant-like property, and modulation of epithelial lining fluid volume. The expression of SPLUNC1 in the lung is dynamic and reflects maturational, functional, and pathological changes in the lung epithelium. We are interested in elucidating mechanisms associated with epithelial cell-mediated tissue remodeling and regeneration after recurrent bacterial and viral infection-induced injury.
2. Development of novel antibiotics to overcome antimicrobial resistance (AMR)
Our effort in identifying the effects of antimicrobial milieu on host defense against respiratory infection resulted in the successful development of next-generation peptide-based antibiotics (PAX) that demonstrate exciting and promising efficacy in overcoming multidrug-resistant (MDR) bacterial infection and sepsis. I have obtained two five-year R01 funding supports from NIAID as PI and another five-year R01 from NIGMS as Co-I to characterize the biological response involved in the disposition of novel antimicrobial agents, define pharmacokinetic information for the development of PAX therapy, and investigate the toxicological effects caused by therapeutic drugs. Our novel PAX’s design, composition, and targeted microorganisms have been granted multiple patents, including two US patents, a European Union (EU) patent, a Chinese patent, and a Canadian patent. My lab also works diligently to develop an alternative approach to elucidating the antimicrobial-resistant mechanisms associated with the standard-of-care antibiotics and host microenvironment; we have developed a novel biofilm assay to investigate bacterial adaptation and evolution with analysis using whole-genome sequencing (WGS), bioinformatics, and CRISPR-based gene editing.
3. Inflammation-associated tissue remodeling and lung tumorigenesis
Our laboratory developed and published an innovative exposure paradigm that demonstrated the synergistic effect of lung tumorigenesis (>8x, p<0.0001) when carcinogens and inflammation co-exist. We reported a higher frequency of lung tumors harboring K-ras mutation by co-exposure to a cigarette smoke carcinogen, NNK, and LPS, an inflammation-eliciting endotoxin from Gram-negative bacteria. We have found that inflammation-associated lung tumorigenesis is differentially regulated by gender and happens with higher frequency and incidence in females than in males. Our inflammation-associated cancer model demonstrated an immunosuppressive environment that promotes T-cell exhaustion and tumorigenesis. We have also used this exciting inflammation-associated lung cancer model to determine the efficacy of checkpoint blockade-based immunotherapy and generated gene signatures that provided high predictive value to anti-PD1 therapeutic response in lung cancer patients.
