Research

Airway cilia stained with antibody against beta-tubulin IV
Our research overlaps cell biology, physiology, pharmacology, immunology, microbiology, and genetics. Our work has been supported by grants from the National Science Foundation, the Cystic Fibrosis Foundation, and the National Institutes of Health. 
    
We study the epithelial cells that line the airway. When airway cell function goes awry, it can lead to diseases such as cystic fibrosis (CF), asthma, chronic rhinosinusitis (CRS), and allergy. To understand how airway cells function, we combine biochemistry and molecular biology with real-time measurements of airway cell signaling and associated physiological responses, including ciliary beating, calcium signaling, fluid secretion, ion transport, nitric oxide production, and antimicrobial peptide secretion. Our goal is to better understand the cellular and molecular bases of airway diseases to identify novel molecular targets for new therapies.

Our research is highly translational. We utilize primary human cells grown from tissue isolated from sinus surgeries. The close partnership we have with physicians at the Hospital of the University of Pennsylvania and the Philadelphia VA Medical Center allows us to take ideas generated in our lab and see them tested or evaluated in a real clinical setting.  

Keywords:  signal transduction, calcium signaling, nitric oxide signaling, cAMP signaling, ciliary beating, ion transport, antimicrobial peptides, chronic rhinosinusitis, cystic fibrosis, diabetes mellitus   


Ongoing Research Topics:

G Protein-Coupled Receptors and Signaling Pathways Regulating Airway Cell Biology, Physiology and Innate Immunity


Cilia beating on nasal epithelial cells
The airway is continuously challenged by inhaled bacteria and viruses.  The nose is at the front-line of respiratory defense, and host-pathogen interactions occur with every breath.  Nevertheless, in most people, the airways remain relatively clean and free of pathological bacterial colonization.

How does the airway successfully defend itself against the onslaught of inhaled pathogens? The primary physical defense is mucociliary clearance. Inhaled bacteria and viruses are trapped by mucus secreted by the airway epithelial cells. Motile cilia (shown above) line the airway epithelium, and coordinated ciliary beating transports debris-laden mucus from the respiratory passages toward the pharynx (throat), where it is cleared by swallowing or expectoration.

Multiple mechanisms protect the airway from infection
  
Efficient mucociliary clearance requires the proper regulation of ciliary beating as well as mucus secretion and fluid homeostasis.  Mucociliary clearance is complemented by the secretion of antimicrobial peptides and the generation of reactive oxygen and nitrogen species (ROS/RNS) that have direct antibacterial and antiviral effects.  

These mechanisms are tightly regulated by G-protein-coupled receptors that respond to host and environmental cues.  Our goal is to understand how airway cells sense and respond to these signals by focusing on airway epithelial cell signaling pathways and the receptors that activate them.  We hope that this research will reveal insights not only into airway physiology but also into the regulation of signaling pathways in all types of cells.  Because GPCRs are among the most heavily researched drug targets, we expect this research to reveal ways to use existing GPCR-targeting compounds to modulate mucociliary clearance, inflammation, or other airway processes.   
       
Motile Cilia as Chemosensory Organelles

Traditionally, mammalian cilia have been categorized into two types: 1) primary or sensory cilia, usually with one single cilia expressed per cell on nearly every cell in the body and 2) motile cilia, usually expressed in high numbers per cell but only on specialized epithelial cells.  Primary cilia have long been known to serve a sensory role, while motile cilia were thought to primarily be responsible for driving the transport of fluid and/or mucus, as seen in the respiratory tract.  However, we and others have now shown that motile cilia also serve a sensory role in epithelial tissue.      

T2R38 activates an antimicrobial pathway
We have recently discovered the expression of T2R bitter “taste” receptors in the cilia of cells in the nose and sinuses.  T2Rs are G-protein–coupled receptors originally identified in type II taste cells of the tongue, where they function to protect against the ingestion of harmful compounds, including toxic bacterial (eg, fermentation) products.    

Activation of T2R receptors within the cilia appears to activate unique signaling pathways.  One of these taste receptors, T2R38, detects compounds from invading bacteria and stimulates a nitric oxide-medaited defense response.  We are interested in studying the sensory role of motile cilia, which sensory receptors are expressed there, and how signaling occurs through receptors localized to the cilia.
  
Chemosensory Signals Involved in Host-Pathogen Interactions in Chronic Rhinosinusitis

We are primarily interested cilia chemo-sensation, because we want to understand how epithelial cells detect the presence of invading pathogens.  A central goal of our research is to elucidate the roles of T2R bitter “taste” receptors in airway physiology and innate immunity to better understand what chemical signals host cells use to differentiate "good" vs "bad" bacteria. 

T2Rs have a uniquely high density of naturally-occurring, well-characterized genetic variants which underlie the complex individual variations in human taste preferences.  Individual genetic differences in T2Rs may create variation in how efficiently airway cells from different individuals “sense” bacteria.  We have hypothesized that genetic variation of T2R receptors may contribute to varying susceptibility to respiratory infections.  We've found that a common polymorphisms resulting in lack of T2R38 function is an independent risk factor for chronic sinusitis (CRS), a disease affecting more than 35 million Americans.