Descripció del projecte
Cystic Fibrosis (CF) is the most common and monogenic disease among the Caucasian population with about 32,000 affected individuals in Europe. CF is caused by mutations in the gen Cystic Fibrosis Transmembrane Regulator (CFTR), a cyclic AMP-regulated chloride channel expressed in the apical membrane of the epithelial cells. It has been reported more than 2,000 pathogenic variants in the CFTR gene but dateF508del is present in around 80% of cases. This disease affects the exocrine glands, giving rise to a wide variety of clinical manifestations and different severity. However, the greatest cause of morbidity and mortality in these patients is due to respiratory disease caused by an impairment in the mucus clearance, leading to bronchial inflammation and regular infections with terminal respiratory failure. Other frequent symptoms in CF patients are pancreas insufficiency and/or male infertility.
The airway surface liquid (ASL) is the thin layer of watery solution that lies between the airway epithelium and the gas in the lumen. ASL plays a key role in airway homeostasis by maintaining ciliary function, mucociliary clearance and antimicrobial properties. ASL volume production reflects a balance between chloride secretion and sodium absorption where CFTR plays a key role. Extracellular adenosine (Ado) acts as a reporter molecule in the ASL whose concentration and dilution serve to modulate CFTR activity via stimulation of purinergic receptors.
In the past years, studies have been evidenced receptor-based pathways that signal through cAMP such as adenosine receptors are relatively accessible candidates for promoting CFTR activation and its modulation could help restore the chloride normal flow affected in cystic fibrosis. Purinergic signalling has been implicated in cellular processes and several diseases, not only in CF. It is growing field where Palobiofarma is one of the main references in the Spanish biotechnology sector and they are focused on drug discovery based on the modulation of adenosine receptor.
The genotype and phenotype variability of CF makes it difficult to standardize therapies among patients. 3D cell cultures such as spheroids and organoids offer new opportunities to better study disease functionality and drug -testing individually. Nasospheroids are 3D spheres formed spontaneously from differentiated nasal epithelial cells obtained by nasal brushing. Intestinal organoids are three-dimensional in vitro structures which mimic intestine structure and function. Nasospheroids and intestinal organoids have been established in Medicine Genetics laboratory of Vall Hebron Institut de Recerca (VHIR) and Clinical & Molecular Genetics Area at Vall Hebron University Hospital (HUVH) in collaboration with the CF Unit (HUVH), one of the most important CF centres in Spain and the only Spanish centre with clinical trials participation.
The project aims to study the functional relationship of adenosine receptors and it’s modulators with CFTR protein. Furthermore, we are interested in study how Palobiofarma molecules can modulate the CFTR cell function. To achieve this, it is necessary: 1) to develop a protocol to study of purinergic receptors in CFTR functional models (organoids and respiratory epithelial cells (Nasospheroids)) 2) to investigate the effect of agonists and antagonists of purinergic receptors in CFTR function and Chloride Conductance 3) to define possible synergies between CFTR modulators and purinergic agonists/antagonists in the functional models established from CF patient cells 4) to characterize genetic variants in the Purinergic receptor genes in CF patients.
