The Fight against Cystic Fibrosis: The European project NEUPROCF presents its results during its final conference

November 26 2008

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NEUPROCF is a European research project dedicated to developing new methodologies for the analysis of bio-markers to improve the prognosis of cystic fibrosis. Coordinated by Inserm (co-ordinating scientist: Mr Aleksander Edelman, CNRS Research Director, team director in Inserm unit 845, Necker Hospital), this project groups together the research teams and clinical departments of 7 European countries (1). Project scientists recently made an appraisal of their 3 years of work at the end of funding within the scope of the 6th PCRDT.

Cystic fibrosis: portal and lobular fibrosis. Dilation of biliary tracts containing mucus.

Cystic fibrosis: portal and lobular fibrosis. Dilation of biliary tracts containing mucus.

Cystic fibrosis is a disease affecting the respiratory tract and gastrointestinal system. Nearly 6,000 patients are affected in France. It is associated with abnormal fluid transport in organs such as the lungs, intestine or pancreas. Cystic fibrosis leads to superinfected chronic inflammatory lung disease which is the main cause of death. The only treatment at the advanced stage of this disease is lung transplantation. Today, 19 years after the identification of mutations in the CFTR gene which cause the disease, there is still no effective treatment.

Treatment of cystic fibrosis requires the institution of new drug therapies. This treatment must be adjusted according to the main characteristics of patients, in particular according to the degree of severity. Ideally, the potential for disease progression should be known very early on, in order to target therapy and provide individually tailored treatment.

For this purpose, NEUPROCF undertook to identify molecules (proteins, lipids) that may represent biomarkers of severity and prognosis. In addition, the researchers developed a strategy based on in silico analysis of the mutant CFTR protein (product of the gene with the same name) in association with experimental data in order to propose new repair molecules. One of the objectives of this project was to study the molecular mechanisms which promote the survival of these inflammatory cells in order, in the long term, to modulate their function and to limit their destructive potential.

Four major advances made in the fields of clinical medicine, fundamental research and methodology

  • The clinical history of 130 patients was studied and prognostic factors of outcome were defined in order to establish a predictive clinical score of disease severity.
  • Dynamic modelling of the CFTR protein fragment containing one of the most important mutations, the F508del mutation, was used to identify potential niches for repair molecules. Systematic computer analysis of several hundreds of thousands of available molecules in "banks" led to the characterization of about fifteen potential repair molecules. Experiments conducted on an "in vitro" cell model identified 4 active molecules. These 4 molecules are currently under study. "This innovative approach may result in real therapeutic progress", explained Mr Edelman.
  • A new method for the analysis of lipids has been developed. This development is, and will be applied to seek lipid markers in cystic fibrosis, and may be used in various fields of fundamental and/or applied research in other diseases. "Such an approach has never been attempted in cystic fibrosis or in any other disease", pointed out Aleksander Edelman.
  • The study of inflammatory cells, in particular neutrophils, has helped demonstrate new mechanisms involved in the survival of these cells, and these mechanisms may eventually be targets of anti-inflammatory therapy.

Lastly, collaboration between French, Polish, and German teams (in particular a small company, Proteosys GMBH) has made it possible to substantially improve the quantitative analysis of proteins by the technique known as mass spectrometry (new method for preparing serum samples, isotopic labelling and computer analysis of data), and the identification of 2 new targets for drug therapy of cystic fibrosis (2 inflammation proteins: annexin1, coronin). These two proteins are in addition to all the other severity biomarkers.


(1) France (Inserm, APHP et Inserm-Transfert), United Kingdom ("University College, London" and "University of Wales, Cardiff"), Sweden ("Uppsala University" and "Karolinska Institute"), Poland ("Polish Academia of Science" and "Institute of Mother and Child", Warsaw), Germany ("Universitätklinikum Ulm" and Proteosys Gmbh,), Portugal ("University of Lisboa"), Czech Republic ("Pragua Hospital")


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Researcher's contact details

Scientific coordinator

Aleksander Edelman
Unité Inserm 845 "Centre de recherche croissance et signalisation", Paris
Tel.: 01 40 61 56 25
Mel : aleksander.edelman@inserm.fr

Références

1. Hinzpeter A, Fritsch J, Borot F, Trudel S, Vieu DL, Brouillard F, Baudouin-Legros M, Clain J, Edelman A, Ollero M. Membrane cholesterol content modulates ClC-2 gating and sensitivity to oxidative stress. J Biol Chem. 2007 Jan 26;282(4):2423-32.
2. BaudouinLegros M, Hamdaoui N, Borot F, Fritsch J, Olllero M, Planelles G,Edelman A. Control of basal CFTR gene expression by bicarbonate-sensitive adenylyl cyclase in human pulmonary cells. Cell Physiol Biochem. 2008;21(1-3):75-86.
3. Brouillard F, Fritsch J, Edelman A, Ollero M. Contribution of proteomics to the study of the role of cytokeratins in disease and physiopathology. Proteomics Clinical Applications 2008 ; 2, Issue 2: 264-285
4. Sermet-Gaudelus I, Souberbielle JC, Ruiz JC, Vrielynck S, Heuillon B, Azhar I, Cazenave A, Lawson-Body E, Chedevergne F, Lenoir G. Low bone mineral density in young children with cystic fibrosis. 2007. Am J Respir Crit Care Med. 175(9):951-7.
Faculty of 1000 Medicine: evaluations for Sermet-Gaudelus I et al Am J Respir Crit Care Med 2007 May 1 175 (9) :951-7
5. Ollero M, Brouillard F, Edelman A. Cystic fibrosis enters the proteomic scene: new answers to old questions. Proteomics. 2006. 6(14):4084-4099.
6. Baudouin-Legros M, Hamdaoui N, Borot F, Fritsch J, Ollero M, Planelles G, Edelman A. Control of basal CFTR gene expression by bicarbonate-sensitive adenylyl cyclase in human pulmonary cells. Cell Physiol Biochem. 2008;21(1-3):75-86.

Invited lecture

- Mac Gill University A. Edelman CFTR interactome : what we can learn from proteomic and in silico analysis.
- North American Cystic Fibrosis Conference: invted lecture by A. Edelman "CFTRE gene expression"

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