Identification of oxidative stress susceptibility-related genes in cystic fibrosis airway epithelial cells through functional genomics using a randomized sirna library
- Autores: Javier Checa Raya
- Directores de la Tesis: Josep Maria Aran Perramon (dir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2021
- Idioma: inglés
- Tribunal Calificador de la Tesis: Carlos Ciudad Gómez (presid.), Antonio Moreno Galdó (secret.), David de Semir Frappart (voc.)
- Programa de doctorado: Programa de Doctorado en Biotecnología por la Universidad de Barcelona
- Materias:
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- Resumen
Cystic fibrosis (CF) is a serious recessive hereditary autosomal disease. It is the most frequent in the Caucasian population and the first cause of chronic pulmonary pathology in the childhood.
CF is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator or CFTR gene, and the produced protein, CFTR, works as a chloride (Cl- ) channel regulated by cyclic adenosine monophosphate (cAMP) in healthy individuals. The CFTR gene was isolated in 19891by positional cloning. The CFTR protein functions as a channel and as a regulatory mechanism. Its function is to regulate the potassium ion (K+) and sodium ion (Na+) transport channels and to activate other oxidative channels that participate in the electrolytes transport2 but the molecular basis for its function as a Cl- selective channel is, by far, the best understood.
The normal CFTR protein is located in the apical membrane of epithelial cells in the several organs involved in CF, including the respiratory, pancreatic and intestinal tissues, sweat gland and reproductive tissues.2 The mutation that is detected more frequently is the deletion of the amino acid phenyalanine in the position 508 (F508del). This mutation is present in 70 % of the individuals with CF (http:// www.genet.sickkids.on.ca/). More than 2,000 mutations affecting the functionality of the CFTR protein have been described until 2020, and more specifically, as of December 7, 2020, 2,103 mutations (http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html), and most of them are little deletions with different effects, such as changes in the reading frame, changes in amino acids, premature termination of the protein or alterations in RNA splicing. The direct consequence of these mutations is the alteration of the activity of exocrine epithelial cells, increasing the Cl- and Na+ fluxes. Thus, CF affects mucus membranes and mainly the lungs, pancreas, liver, paranasal sinuses and sexual organs and causes increased levels of Cl-and Na+ions in the sweat.3 Even though many pathologies related to CF have been reported, such as severe maldigestion,4 male infertility,5 or salt loss syndroms,6respiratory dysfunction, secondary to chronic lung infection caused by recurrent bacteria and the subsequent inflammation, is the main clinical consequence of these pathogenic events in more than 90 % of the CF patients which exceed the neonatal period.7,8 Thus, abnormal CFTR function leads to the production of dense and viscous mucus that obstruct the airway. The final result is a dehydration of the respiratory ciliated epithelium that prevents the correct gliding of the mucus trough the tracheobronchial respiratory tree.9,10 During the last years there has been an important improvement in the quality and expectancy of life in CF patients.11 In the 90s, estimates indicated already an increase in life expectancy close to 40 years.12 The main factors that have contributed to this have been early diagnosis of the disease, prompt identification and treatment of the complications related to CF, nutritional support, implementation of effective hygienic measures inside and out of the CF centers, improvements in antibiotic treatments, respiratory physiotherapy, lung transplantation, a better care organization in medical centers and, recently, new therapies like CFTR modulators (correctors and potentiators).
