Mechanisms of epithelial transport in health and disease

My research program focus on the mechanisms of epithelial solute transport, its regulation by extracellular and the intracellular signals, and the pathological consequences of transport failure.  Currently we have two main research programs involving:

1) Cystic fibrosis airway disease pathobiology:

Cystic fibrosis (CF) is the most common, fatal genetic disease affecting young Canadians. CF is an autosomal recessive condition caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. It is estimated that one in every 3,600 children born in Canada has CF and approximately one in every 25 Canadians carries a defective version of the gene responsible for CF. Thanks to advances in research and clinical care, growing numbers of children with CF are surviving into adulthood. In 1960 the median age of survival of Canadian patients with CF was 4 years; today, it is 37 years of age. However, controversies still surround the pathogenesis of airway disease. We lack answers to many questions and CF remains a lethal disease, thus, current treatments are inadequate.

The main objective of my research program is to study the link between the mutation of CFTR and the failure in CF patients of the innate defence mechanisms that normally protects airways from infection. There is evidence showing that cystic fibrosis lung disease reflects the failure of the innate defense mechanisms of the lung against inhaled organisms such as Pseudomonas aeruginosa. Normal airways are protected from inhaled ‘insults’ by a complex immune defense system that includes mucus containing antimicrobial factor that traps and inactivates bacteria favoring clearance from the airways.

Specific research aims:

  1. Response of airway submucosal glands to proinflamatory cytokines
  2. Stimulation of mucus secretion by bacteria inhalation by swine in vivo  using synchrotron light

2) Molecular and cellular mechanisms of epithelial transport:

The laws of thermodynamic govern the direction and rate of movement of solutes across epithelial cells, i.e. down the electrochemical gradient for any molecule. The fundamental function of transporting epithelia is to generate the electrochemical gradients that will force movement of molecules in the desired direction. This is achieved by the asymmetrical distributions of transport systems (channels, ATPases, cotransporters and exchangers) in the apical and basolateral membranes of polarized epithelial cells. Primary active transport by ATPases generates electrochemical gradients that are exploited by membranes with selective permeability to produce unidirectional movement of solutes that would otherwise be thermodynamically unfavorable.

Our lab seeks to understand the molecular and cellular mechanisms that allow that transport machinery to work in unisons using the insect models Drosophila melanogaster and Rhodnius prolixus Malpighian (renal) tubule.

Specific research aim:

  1. The role of intracellular Ca2+ in the cross-talk between apical and basolateral transporters in Rhodnius prolixus Malpighian tubules