Robert J. Lee, PhD

Assistant Professor of Otorhinolaryngology: Head and Neck Surgery

Assistant Professor of Physiology

Lab Web Site

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1209 BRB II/III

421 Curie Boulevard

Philadelphia, PA 19104

215-573-9766

rjl@mail.med.upenn.edu

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Robert J. Lee, PhD


Assistant Professor of Otorhinolaryngology: Head and Neck Surgery and Physiology (Secondary)

Other Perelman School of Medicine Affiliations


Degrees & Education

  • BS (Molecular Biology), University of Pittsburgh, PA, 2003

  • PhD (Cell and Molecular Biology), University of Pennsylvania Perelman School of Medicine, PA, 2008


Awards & Honors

  • Ann Weinberg Memorial Postdoctoral Research Fellowship , Cystic Fibrosis Foundation (2009-2011)

  • Best Lecture Prize, 8th Annual Biomedical Postdoctoral Symposium, Univ, of Pennsylvania (Oct. 2009)

  • National Science Foundation Graduate Research Fellowship (2004 - 2007)


Professional Affiliations

  • University of Pennsylvania Institute for Translational Medicine and Therapeutics

  • American Society for Cell Biology

  • American Society for Microbiology

  • American Physiological Society

  • American Medical Writers Association


Research Interests

  • Airway cell biology and physiology, Extra-oral taste receptors, Regulation of motile cilia, Epithelial ion transport and fluid secretion, Bicarbonate Secretion, Innate immunity

Keywords

  • signal transduction, chronic rhinosinusitis, cystic fibrosis, live cell imaging, calcium and nitric oxide signaling, antimicrobial peptides


Research Description

We study the physiology of the epithelial cells lining the upper airway (nose and sinuses), to understand how they sense and respond to pathogens. We combine biochemistry and molecular biology with real-time optical 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.

Chronic upper respiratory infections can result in chronic rhinosinusitis (CRS), a disease affecting 8-10% of the US population with direct healthcare costs of over 6 billion dollars annually. CRS has a major impact on individual quality of life as well as on public health; CRS accounts for 1 out of every 5 antibiotic prescriptions in adults in the US, making its treatment a major contributor to the emergence of antibiotic-resistant organisms. A continuing goal of our research is to identify new and better therapies to treat CRS and other airway diseases without the use of antibiotics, particularly through the stimulation of endogenous innate immune pathways.

Our research is highly translational. The close partnership we have with physicians at the Hospital of the University of Pennsylvania and the Philadelphia VA Medical Center allows ideas generated in our lab to be directly tested or evaluated in a real clinical setting.


Specific Areas of Focus

Regulation of Mucociliary Clearance: The primary physical defense of the airway is mucociliary clearance. Inhaled bacteria and viruses are trapped by mucus secreted by airway epithelial cells. Motile cilia line the airway, and coordinated ciliary beating transports debris-laden mucus from the respiratory passages toward the pharynx (throat), where it is cleared by swallowing or expectoration.

Efficient mucociliary clearance requires the proper regulation of ciliary beating as well as mucus secretion and fluid homeostasis. When mucociliary clearance is not enough, it 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 receptors that respond to host and environmental cues. Our goal is to understand the basic science of airway epithelial cell signaling pathways and the receptors that activate them.

Role of Taste Receptors in Motile Cilia: How do airway epithelial cells detect the presence of invading pathogens? We recently discovered that this occurs partly through T2R bitter “taste” receptors in the cilia of epithelial 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. One specific bitter taste receptor, T2R38, detects quorum-sensing compounds from invading bacteria and stimulates a nitric oxide-mediated innate immune defense response. Our observations suggest that bitter taste receptors are an “early warning” arm of airway innate immunity, activating responses within seconds to minutes of sensing these bitter bacterial products.

Moreover, T2Rs have a uniquely high density of naturally-occurring, well-characterized genetic variants (polymorphisms) which underlie the complex individual variations in human taste preferences. We have hypothesized that individual genetic differences in T2Rs may create variation in how efficiently airway cells from different individuals “sense” bacteria and contribute to varying susceptibility to respiratory infections. In support of this, through our partnership with physicians at HUP and the Philadelphia VAMC, we've found that a common polymorphism resulting in lack of T2R38 function is an independent risk factor for CRS.

Role of the Sweet Taste Receptor in Airway Physiology: Sweet taste (T1R) receptors are expressed in specialized solitary chemosensory cells in the sinonasal epithelium. These T1R sweet receptors in the nose may function as a “rheostat” to control the magnitude of T2R-dependent antimicrobial responses based on bacterial population density. The sweet receptor may desensitize solitary chemosensory cells to bitter compounds secreted by some bacteria during low-level colonization, but during the onset of a bona fide infection, an increase in bacterial numbers and bacterial consumption of the glucose in the airway mucus (normally about 10-fold lower than serum levels), de-activate T1R sweet receptors, and allow T2R receptors to stimulate defensive responses.

Based on this hypothesis, the sweet receptor in the nose may have important clinical relevance for CRS and diabetes. In patients with diabetes mellitus, increased blood glucose levels are known to increase airway mucus glucose levels. We also found that CRS patients have elevated nasal mucus glucose, likely due to increased leak from damage to their epithelial tissues as a result of chronic infection and inflammation. Diabetics are more prone to airway infections than non-diabetics, and this may potentially be due to higher nasal mucus glucose that overly-inhibits the airway solitary chemosensory cell defensive response.


Lab Members

Maureen Victoria (lab manager/research specialist), Derek McMahon (postdoctoral fellow), Ben Hariri (year-out post bac student)

Click here for a full list of publications.
(searches the National Library of Medicine's PubMed database.)


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