Research
Cystic Fibrosis (CF) is a rare recessive genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a chloride channel that influences the composition and quantity of liquid at the surface of epithelia of most exocrine tissues. In the lungs, absence or dysfunction of the CFTR protein results in altered epithelial salt and water transport resulting in impaired mucociliary clearance, chronic infection, exuberant inflammation and tissue damage. Pseudomonas aeruginosa is the most commonly identified microorganisms in CF respiratory samples worldwide and, despite the inflammatory response, persists in CF lungs leading to poor lung function, morbidity and mortality.
My research program is translational, from the patient to basic physiopathologic research, and vice versa, with an overall objective to define personalized CF care and treatment strategies. The major aims are:
identification and functional genetics of modifier genes
Although CF is recognized as a single gene disorder, considerable phenotypical diversity exists among patients with the same CFTR mutations. Besides environmental factors, it has been shown that additional genetic modifiers contribute to this variability. It has been previously estimated that 50% of the lung function variance is attributable to non-CFTR genetics factors. We recently identified several modifiers in our past genetic studies.
The variation of patient’s drug response may be genetically influenced. Currently, pharmacogenomics studies are ongoing in patients receiving CFTR-targeted therapies. Also, functional genetics is being performed to obtain insights on the functional consequences of the genes and variants identified through these genomics studies. As in the majority of GWAS-identified variants in various diseases, the SNPs that will be identified could fall in noncoding regions of the genome, as the SNPS on GWAS chips are chosen based on linkage disequilibrium patterns and coverage. Thus, the functional analyses consist on studying the genes per se, the majority being not well characterized, especially in the CF context. In order to study the contribution of one gene to a given phenotype, gain or loss of function experiments with specific tools (CRISPR/Cas9, siRNA…) are considered.
ncRNA and airway response to Pseudomonas aeruginosa
Even if new drugs targeting CFTR are improving the lung function of some patients, bacterial resistance outburst is still not resolved highlighting the need for innovative therapies. In the course of their disease, CF patients are colonized with several bacterial strains, particularly Pseudomonas aeruginosa, which is associated with lung function decline.
In this context, a better characterization of the response of the airway epithelium, the first barrier of defense against Pseudomonas aeruginosa infection is a necessary and a critical first step, in order to define better anti-infective strategies and to propose alternative treatment than antibiotics that have shown their limits of actions in CF due to antibiotic resistance.
We are currently addressing a novel and important aspect of respiratory epithelial cell host response: the role of two classes of non-coding RNAs (ncRNAs), the long non-coding RNAs (lncRNAs) and the microRNAs (miRNAs) in the course of infection against Pseudomonas aeruginosa in CF. Understanding respiratory epithelial cell responses to Pseudomonas aeruginosa at the ncRNA level and the functionality of these ncRNAs could lead to identify new molecular targets to enhance mucosal defense of CF patients.
Control of the growth of Aspergillus fumigatus by human bronchial epithelial cells
Among the fungi present in the sputum of patients with cystic fibrosis, Aspergillus fumigatus (Af) is the most common species found with a prevalence ranging from 10 to 50%. Its persistence may cause allergic bronchopulmonary aspergillosis and aspergillar bronchitis responsible for a deterioration in respiratory function. The mechanisms by which Af chronically colonizes patients' airways are poorly understood to date.
We have shown and published that bronchial epithelial cells are capable of inhibiting Af filamentation by a PI3 kinase-dependent process. We have identified that the recognition of Af by epithelial cells via lectin, FleA expressed by spores, was involved in this anti-fungal activity.
Our objective is now to identify the cellular receptor interacting with this lectin, to understand its mechanism of action and to study the expression and activity of the various partners involved in this anti-fungal activity in the context of CF.
As a whole, this project is ambitious and an attractive challenge in the CF context. It represents a tremendous opportunity in the global comprehension of CF and will help to translate these new genetic and host response insights into better strategies for prevention and treatment of CF patients. Survival in population is multifactorial, including better diagnosis, phenotype characterization and treatment. To extend the survival and quality of life for CF patients, specific therapies targeting CFTR have been developed largely due to the translational research pipeline from basic science to clinical research. In line with this translational approach, the present research gives an unprecedented opportunity to develop new paths with possibilities to diagnose and cure CF patients.
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