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Approaches to Pharmacological Treatment and Gene Therapy of Cystic Fibrosis
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cystic fibrosis (CF) is the most common lethal genetic disease in the white population. It is due to mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), a protein that functions mainly as a cAMP-activated chloride channel. The disease impairs ion and water transport in epithelia-lined organs such as airways, digestive tract, reproductive epithelium and sweat glands. At present the only therapy is symptomatic and development of curative treatment depends on uncovering the links between the defective CFTR and the disease, as well as on improving end-point measurements.

A method has been established for studying ion transport in an easily accessible cell type (nasal epithelial cells) from normal and cystic fibrosis patients by X-ray microanalysis. This method represents a rather simple and direct way of measuring simultaneously several chemical elements of biological interest.

Studies of chloride transport by means of a fluorescent indicator (MQAE) in nasal epithelial cells from CF patients showed that the phenotype cannot exclusively be explained by the CFTR activity in patients with severe genotype.

A common Portuguese CFTR mutation (A561E) causes protein mislocalization in the endoplasmic reticulum similar to the most common CF mutation (ΔF508) and thus it should be possible to treat it with the same pharmacological strategies.

Chronic treatment of CF airway epithelial cells with nanomolar concentrations of colchicine increased the chloride efflux via chloride channels other than CFTR, strengthening the notion that colchicine could be beneficial to CF patients.

Successful in vitro transfection of CF airway epithelial cells with cationic vectors was possible with short incubation times. Heparin added at the end of the transfection incubation time could help to maintain the viability of the cells, without interfering with the transfection efficiency. It seems possible that heparin could be an adjuvant for non-viral mediated gene therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 51
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1312
Keyword [en]
Anatomy, airway epithelium, colchicine, cystic fibrosis, chloride transport, genotype, heparin, phenotype, transfection, X-ray microanalysis
Keyword [sv]
Anatomi
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-3845ISBN: 91-554-5822-X (print)OAI: oai:DiVA.org:uu-3845DiVA, id: diva2:163786
Public defence
2004-01-16, B21, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-12-17 Created: 2003-12-17 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Assessment of chloride secretion in human nasal epithelial cells by X-ray microanalysis.
Open this publication in new window or tab >>Assessment of chloride secretion in human nasal epithelial cells by X-ray microanalysis.
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2001 In: Journal of Microscopy, Vol. 203, no 3, p. 277-284Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91153 (URN)
Available from: 2003-12-17 Created: 2003-12-17Bibliographically approved
2. Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes.
Open this publication in new window or tab >>Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes.
2002 In: Clinical Science, Vol. 103, p. 417-424Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91154 (URN)
Available from: 2003-12-17 Created: 2003-12-17Bibliographically approved
3. Unusually common cystic fibrosis mutation in Portugal encodes a misprocessed protein.
Open this publication in new window or tab >>Unusually common cystic fibrosis mutation in Portugal encodes a misprocessed protein.
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2003 In: Biochemical and Biophysical Research Communications, Vol. 311, p. 665-671Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91155 (URN)
Available from: 2003-12-17 Created: 2003-12-17Bibliographically approved
4. Colchicine increases the chloride efflux in airway epithelial cell lines.
Open this publication in new window or tab >>Colchicine increases the chloride efflux in airway epithelial cell lines.
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91156 (URN)
Available from: 2003-12-17 Created: 2003-12-17Bibliographically approved
5. Heparin can improve the viability of transfected cystic fibrosis cell lines in vitro.
Open this publication in new window or tab >>Heparin can improve the viability of transfected cystic fibrosis cell lines in vitro.
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91157 (URN)
Available from: 2003-12-17 Created: 2003-12-17Bibliographically approved

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