The Holtzman Lab studies the role of respiratory viruses in causing acute and chronic disease, focusing on antiviral immune responses as pathways for pathogenesis and targets for drug discovery. We apply a multidisciplinary and translational approach to study cellular and mouse models as well as human subjects.
We have shown that viral immunity depends on a special network of innate immune-response genes in host cells of the airway epithelial barrier, and we have focused on this network as a drug target for antiviral therapy. In particular, we have engineered the interferon-signaling pathway to better control viral replication and have applied this strategy to new and emergent viruses in cell and animal models.
We have extended this strategy to discovery of small molecules with interferon-enhancing and antiviral efficacy that have just reached the stage of human clinical trials. We have also found that viruses activate a distinct immune axis that includes a distinct epithelial stem cell niche and a novel set of innate immune cell interactions in experimental models and in human subjects with chronic respiratory diseases such as asthma and COPD. This pathway leads to excess airway mucus production that is incriminated in the morbidity and mortality from these diseases, now the third leading cause of death in the U.S. To address this issue, we have also targeted this pathway for drug discovery using structure-based drug design to identify proprietary small molecules that interrupt kinase-dependent mucus production, thereby providing tool compounds for proof-of-concept and lead candidates for clinical application.Current efforts also include defining the epigenetic basis of epithelial stem cell reprogramming after viral infection to develop cell-based therapy for airway disease.
Projects:
- Interferon signal transduction
- Epithelial stem cell programming
- Innate immune response
- Post-viral disease
- Anti-viral and anti-mucus drug discovery