Research Interests

Cell & Molecular physiology; respipratory physiology; ion channels structure & functions
Cystic Fibrosis (CF) is the most common lethal genetic disease in North American and European populations, affecting 1/3,500 Canadians. Mutations in the CFTR gene, which conduct to the absence or dysfunction of the CFTR chloride channel, are widely spread in the population. 1 in 25 Canadian is a healthy carrier of 1 mutation in the CFTR gene. It is thus crucial to understand how the CFTR channel functions to maintain healthy lungs and digestive system before being able to develop specific therapies that will correct the molecular defect responsible for this devastating disease.
Research conducted in my laboratory aim to develop strategies to correct the dysfunctional protein (CFTR) responsible for this disease. We study the molecular mechanisms that underlie CF, using human and mouse models. We investigate the impact of CF causing mutations on the CFTR protein function and regulation in epithelial cells. We also develop new strategies to reverse the pathological effects of CFTR dysfunction, noteworthy by stimulating specific receptors of the Vasoactive Intestinal Peptide (VIP) and signalling cascades in epithelial cells.

Other aspects of research conducted in my lab are related to the epidemiology of Cystic Fibrosis in the Maritimes. ~250 patients are affected by CF in our Provinces. In collaboration with the local CF clinic and Réseau Santé Nouvelle-Ecosse we have analysed the molecular and phenotypic aspects of mutations found in local patients, together with the prevalence of rare mutations. We are now conducting molecular studies of recombinant CFTR channels with rare mutations found at high prevalence in the local population.

Specific ongoing projects:

Contributions of the Vasoactive Intestinal Peptide (VIP) in the development and progression of respiratory diseases.
Healthy lungs require the presence of an undamaged and well functioning protective layer of cells: the respiratory epithelium. In diseases, such as cystic fibrosis or bronchial asthma, the respiratory epithelium is inflamed and damaged, in part due to excessive mucous production caused by a hyperactivity of submucosal glands, which normally secrete protective fluids under the control of various hormones, among which the Vasoactive Intestinal Peptide (VIP). In healthy individuals, VIP is released from nerves surrounding the airways where it exerts multiple functions, including the control of inflammation, relaxation of smooth muscles and regulation of the CFTR protein. When the CFTR protein is not functional, such as in the genetic disease cystic fibrosis, the protective mucous secreted by the airway's glands is severely altered in its composition. It becomes thick, viscous and difficult to clear. This dense material then starts plugging the airways, promoting chronic bacterial infection and inflammation, and provoking lungs damages which can conduct to respiratory failure. CFTR dysfunction is also suspected to play an important role in airways damages seen in severe bronchial asthma or cigarette smoke. Research conducted in our laboratory focus on the understanding, at the cellular and molecular level, of how the absence from the airways epithelium of functional CFTR contributes to the development of severe respiratory diseases. We study the cell signaling cascades involved in the CFTR/VIP partnership to determine at the molecular level how the absence or a low level of VIP contributes to the development of respiratory diseases and lungs damages. We also use VIP treatments to prevent damages or restore normal lungs function in mice models of bronchial asthma and cystic fibrosis. Our research provides fundamental knowledge to envision therapeutic strategies for multiple respiratory diseases, based their molecular link.

Regulation of CFTR function and membrane stability by Vasoactive Intestinal Peptide treatment: rescue of DF508-CFTR channels.
VIP is the major physiological agonist for CFTR-dependent secretion in exocrine epithelia (lung, intestine, and pancreas). In human bronchial or nasal epithelial cells, we investigate the effect of VIP stimulation on CFTR activity and its stability at the apical membrane. Our results have shown that CFTR-dependent chloride secretion can be increased (wild-type CFTR) or even restored (in human CF cells, DF508-CFTR) by prolonged treatment of epithelial cells with VIP. Using human and mouse models, we are now investigating the mechanism by which VIP can regulate CFTR-dependent chloride secretion and restore normal CFTR function in CF tissues.

Structure/function study of the CFTR (ABCC7) chloride channel.
ABC transporters form one of the largest super family of membrane proteins that are found in all organisms from bacteria to humans. They use the energy generated by ATP binding and hydrolysis to translocate, across cellular membranes, a wide variety of substrates including ions, sugars, vitamins, lipids, amino acids, peptides and proteins. The 48 human ABC proteins are mostly exporters involved in secretion, drug detoxification, and antigen presentation. The C subfamily of eukaryotic ABCs includes several members essential for physiological processes such as the regulation of salts and water movement across epithelial cells of the lungs, pancreas, intestine and reproductive tract (ex: CFTR) or detoxification of the organism (ex: MRP1). Among the thousands of ABC transporters, CFTR or ABCC7, is the only ion channel. Research conducted in my lab, using the CFTR protein as a model of asymmetric eukaryotic ABC exporters, aims to elucidate fundamental aspects of CFTR function which are specific to the asymmetric mode of transport. Molecular and functional studies, as developed in this research program, are used to propose new physiological models on CFTR structure-function relationship and evaluate divergence and similarities with other ABC transporters.
By combining biochemical, cellular, molecular and biophysical techniques we analyze multiple aspects of the CFTR chloride channel structure-function relationship to answer the actual most critical questions on the role of phosphorylation in domains interactions and CFTR gating. Results are used to generate molecular models of CFTR regulation by protein kinase A and C.

Molecular classification and characterization of rare mutations of CFTR with high incidence in the Maritimes.
When we initiated this project, no study had yet been conducted on the molecular profile and phenotype/genotype correlation for CF patients at the local CF clinic which follows ~250 patients for the 3 provinces of the Maritimes. A mutational profile database was thus created in collaboration with nurses and clinicians. We also included important information like the age at diagnosis and critical health parameters with the aim of comparing the severity of the phenotype with the molecular profile. Several rare mutations, some unique in Canada, with a high incidence in the Maritimes were found. Some of these rare mutations highlighted by our analysis have never been studied at the molecular level. We thus decided to select the most prevalent one: P67L and started its molecular analysis to gather some of the critically missing molecular knowledge to set the basis that will enable the development of targeted drug design. A second aspect of this project concerns the profile of Cystic Fibrosis in the Maritimes with special emphasis on the evaluation of the prevalence and awareness of CF in the Acadian and Francophone communities of Nova Scotia, New-Brunswick and Prince Edward Island, for whom no data exist on their specific situation and needs.
The goals of this project are to study the profile of CF patients at the local clinic to better understand the correlation between genetic mutations and the severity of the disease; to develop molecular and clinical studies aimed at discovering new targeted therapeutic strategies and to define the prevalence of CF among Acadians and Francophones of the Maritimes to determine if a particular situation exists.