Manitoba Chemosensory Biology Research Group

Includes research on taste receptor biology, taste disorders, food chemistry and elucidation of novel taste blockers.

Taste receptor biology

Taste receptor cells present in taste buds on the tongue express a number of membrane proteins that mediate taste sensation.

In humans, bitter taste is one of the five basic taste sensations and is mediated by 25 bitter taste receptors (T2Rs).

Recent studies from our group and others have shown that T2Rs are also expressed outside the tongue, including many extraoral tissues such as brain, airways, vasculature, and in pathophysiological conditions such as breast cancer.

This suggests that T2Rs possess as yet largely uncharacterized cellular and physiological functions that are in addition to taste sensing.

A major focus of our group is on studying the role of these chemosensory receptors in airway diseases such as Cystic Fibrosis and in certain types of cancers.

Identification of novel bitter ligands

Structure-function analysis of T2Rs is also an area of intense investigation by our group members.

Most of the T2Rs are activated by a wide variety of plant derived bitter compounds including peptides and advanced glycation end products (AGEs). Therefore, customized proteolysis could be used to generate peptides that activate or deactivate T2Rs.

By studying the effects of different peptides, it will be possible to elucidate the structural requirements that determine T2R-activation or deactivation potency of natural peptide sequences.

Similarly, AGEs can be custom-produced through optimized in vitro reactions between sugars and peptides followed by structure-function studies.

Therefore, a major focus of the research is to determine the structure-function properties of natural peptides and AGEs as T2R agonists or antagonists.

Includes research on bacterial biofilms, efflux pumps, quorum sensing, and bacteria-host cell communications with a specific focus on cystic fibrosis.

Inter-kingdom signaling

In contradiction of the traditional view of bacteria being non-communicating primitive organisms, recent advances in bacteriology prove that bacteria do possess cell-cell chemo-sensing mechanisms.

Bacterial cells communicate with each other using small molecules, such as Acyl-Homoserine Lactones (AHL) and oligopeptides to coordinate population behaviours such as biofilm formation and swarming motility.

Such cell-cell communication is termed as quorum sensing, and is central to the pathogenicity of many bacterial pathogens.

Bacteria also use AHLs and other small molecules to interact with mammalian host cells, and modulate inflammatory and immune responses, a process termed as inter-kingdom signaling.

Such chemosensation between bacterial cells with the host is an exciting new area of research for understanding bacterial pathogenesis and the pathogen-host interactions.

Collaborative research within MCSB currently investigates the interactions between bacterial AHL signal molecules and human airway cells.

The possibility that T2Rs serve as the mediators of AHLs on lung epithelial cells is being explored.

T2R activation by bacterial signals is monitored using real-time cellular analysis techniques.

Bacterial type III secretion system which alters host cell behaviours by injecting bacterial toxins directly to mammalian cells is also being investigated to delineate the signal transduction and pathophysiological interactions between pathogenic bacteria and the host.

Both new knowledge and basis for new technology can be anticipated from this research.

Efflux pumps, antibiotic resistance and chemosensation

One of the most important mechanism of intrinsic antibiotic resistance in Gram-negative bacterial species like Pseudomonas aeruginosa is through the activity of energy-dependent efflux pumps, particularly those belonging to the Resistance-Nodulation-Division (RND) pumps.

One fascinating characteristic of RND pumps is their broad-substrate profile.

Apart from pumping out structurally unrelated antibiotic molecules, they are also believed to efflux molecules involved in quorum sensing or their precursors.

Our collaborative work with other members of the MCSB group involves studying the role of RND efflux pumps in chemosensation between pathogens and the host and thereby understanding the role of these pumps in interplay between virulence and antibiotic resistance.

Focus on signal transduction by chemosensory proteins that are druggable targets (GPCRs), small G proteins, and studying protein-drug interactions.

G protein-coupled receptors (GPCRs) are the targets of >30% of the prescription drugs. There are more than 700 GPCRs in humans and majority of these belong to Class A. Our studies over the past decade focused on Class A GPCRs and small G proteins.

Building on this, we are now interested in pursuing the following research areas involving a few Class A GPCRs, and small G proteins.

• Identification and characterization of new ligands and/or protein interaction partners using computer-aided virtual ligand screening and structure-function analysis.
• Developing GPCR based immunoassays using our overexpression systems and unique immobilization chemistry.
• Studying the “ligand-GPCR-small G protein” signal transduction pathways.
• Elucidating the pathophysiological role of these proteins in certain clinical conditions.

Research on pharmacogenomics, studies relating to the association between caries and taste in children and adolescents, and palatability of oral formulations.

The pulmonary circulation has idiosyncratic responses to many existing vasoactive agents, and many GPCR signal systems understood to act in the oral cavity and airway may also have functions in the pulmonary circuit.

Neonatal circulatory transition involves a tightly regulated series of pulmonary vasodilator signals, many of which are disabled in the context of hypoxia or inflammation.

We have developed excellent model system to study the developmental pharmacology of pulmonary-active GPCRs in vitro, ex vivo and in vivo.

The following areas of research can be explored using MCSB infrastructure and expertise:

• Taste GPCR distribution, function and developmental pharmacology in the pulmonary circuit.
• Search for novel ligands for known pulmonary vasodilator GPCRs or activators of downstream signaling pathways.
• Explication of pulmonary arterial effects of GPCR-mediated airway or vascular smooth muscle relaxants.

Chemosensation and oral health

The areas of research our group is interested in pursuing are:

• Explore the relationship between taste and prevalence of early childhood caries.
• Explore the relationship between taste and dental caries in children, adolescents, and adults.
• Explore the relationship between taste perception and future caries-risk.
• Improve the palatability of clinical dental products.