Bridges immunology, genomics research and bioinformatics to develop a deeper understanding of asthma pathogenesis.
Asthma has reached epidemic proportions, affecting almost 10 percent of the developed world, yet no curative therapeutics exist. The disease encompasses a broad collection of heterogeneous subtypes with a range of underlying causes, including the abnormal function of T helper cells and airway epithelial cells.
MicroRNAs and long non-coding RNAs (lncRNAs) have the capacity to regulate gene expression programs, and their differential expression within immune cells highlights their potential in defining immune cell identity and function. My laboratory focuses on understanding the role of non-coding RNA in controlling immune cell development, differentiation and function in asthma. This work will enable the definition of asthma subtypes, identify mechanisms driving asthma susceptibility, and reveal novel targets for therapeutic intervention. Our major areas of focus are described below.
Transcriptional profiling of blood represents a minimally invasive method to assess immune function. Non-coding RNAs display restricted expression patterns and serve as unique cellular markers. Blood transcriptional profiling that includes analysis of non-coding RNA has the potential to provide a more accurate definition of immune cell status in vivo.
The traditional view of asthma as a Th2-mediated disease is now regarded as overly simplistic, and clinical trials blocking Th2 cytokines have yielded disappointing results, potentially due to mismatches between treatment modalities and the currently poorly defined asthma subtypes. We will therefore use transcriptional profiling of peripheral blood mononuclear cells (and potentially serum itself) to define asthma subtypes and to develop appropriate methods to pre-screen patients accurately.
Re-educating the immune system to induce allergen tolerance potentially offers the best hope for curing asthma. Such treatments are most likely to work in children due to a limited period of allergen exposure; however, early diagnosis of asthma in children is difficult. Diagnostic methods to clearly identify and subtype asthma in children need to be developed. To this end, my laboratory will screen blood from pediatric samples to look for evidence of asthmatic gene expression signatures (as originally defined in adults). If successful, this will allow early identification of allergic susceptibility and initiation of appropriate treatment modalities.
As lncRNAs typically display greater cell-type specific expression patterns than do proteins, lncRNA-directed therapeutics are predicted to cause fewer off-target effects. Airway delivery of locked nucleic acids (LNA) or small molecule inhibitors, to modulate lncRNA function, in combination with existing and/or novel therapies could significantly improve the treatment of asthma. However, before lncRNA-based therapies can be developed, we must first understand their biological function. My laboratory aims to identify, characterize and validate lncRNA-driven pathways active in allergy-driving helper T cells and airway epithelial cells that could hold promise as therapeutic targets in altering the aberrant immune responses underlying asthma.
The CRISPR/Cas9 genome-editing technology allows the rapid generation of genetically modified animals as well as controlled genetic modification in cell lines and primary cells. Therefore, to assess biological function, my laboratory will use this technology to delete candidate lncRNAs or introduce disease-associated polymorphisms in human cell lines and primary cells from healthy volunteers. LncRNAs that affect cellular development and/or function can form the foundation of future studies to develop potential therapeutics.