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Molecular Medicine Partnership Unit |
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Team 2 |
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Pathogenesis and treatment of cystic fibrosis
Factsheet [PDF]
Previous and current research
Cystic fibrosis [CF] is caused by mutations in the cystic fibrosis transmembrane conductance regulator
[CFTR] gene and belongs to the most common lethal hereditary disease in Caucasians. It
is well established that mutations in CFTR cause a characteristic defect in epithelial ion transport
[i.e. decreased cAMP-mediated Cl- secretion and increased Na+ absorption]. Surprisingly, CFTR
knockout mice lacked the basic airway ion transport defect and the chronic lung disease that is
life-limiting in CF patients. Therefore, the progress in our understanding of CF pathophysiology
and the development of effective treatments for CF has been hampered by the lack of an animal
model. Before we joined the MMPU, our individual groups already had a longstanding interest in
research related to the pathogenesis and treatment of cystic fibrosis.
The prior focus of Carsten Schultz was on the development and in vitro testing of small molecule
compounds that target the basic ion transport defect in CF. This work resulted in membrane-permeant
derivatives of myo-inositol 3,4,5,6-tetrakisphosphate, a class of compounds that have been
shown to counteract the basic ion transport defect in CF [Moody, M. et al, Am. J. Physiol. Cell
Physiol., 2005; Traynor-Kaplan, A.E. et al, Adv. Exp. Med. Biol., 2005].
Marcus Mall has previously conducted basic and translational research projects investigating the
correlation between CFTR genotype, CFTR-mediated ion transport in native human epithelia,
and the CF phenotype [Hirtz, S. et al, Gastroenterology, 2004]. In addition, he has recently developed
a novel transgenic mouse model with airway-specific overexpression of epithelial sodium
channels [ENaC]. This mouse model recapitulates increased airway sodium absorption observed
in CF patients, and demonstrated that dehydration of airway surfaces causes a severe spontaneous
CF-like lung disease that shares many common features with CF in humans, including airway
mucus obstruction, goblet cell metaplasia, chronic inflammation and susceptibility to bacterial
infection [Mall. M. et al, Nat. Med., 2004].
Future projects and goals
We joined the MMPU in 2006 to coordinate our efforts in cystic fibrosis research, and will pursue
the following projects. Firstly, we will make use of our established ENaC overexpressing
mouse to test the effects of novel therapeutic modalities for the treatment of CF-like lung disease
in vivo. These studies focus on ENaC inhibitors and activators of alternative calcium-activated
chloride channels [CaCC], including the lead compounds previously synthesized in the Schultz
lab, as well as novel derivatives. Clinical endpoints to determine the therapeutic effects of compounds
on lung disease will include inhibition of airway mucus obstruction, inhibition of pulmonary
inflammation, and reduction in pulmonary mortality.
Secondly, we are currently developing fluorescent methods to monitor CF-relevant epithelial signaling
pathways in vitro and in vivo. Apart from a better understanding of intracellular signalling,
the goal of this project is to provide a platform for testing potential CF drug candidates in a way
that considers as much as possible of the underlying biological system. As a long shot, we aim for
experiments in primary cultures, as well as in transgenic mice expressing fluorescent reporters
that can monitor these intracellular signaling events in vivo. We predict that the interdisciplinary
approach of our MMPU group will significantly contribute to a better understanding of the
pathogenesis and pre-clinical development of more effective therapies for CF. If we identify an
efficient novel treatment strategy for CF lung disease in our animal model, our long term goal is
to initiate clinical trials to translate this treatment into the clinic.
Members:
Dr. Carsten Schultz
Group Leader, Gene Expression Unit
European Molecular Biology Laboratory
Meyerhofstraße 1
69117 Heidelberg
Tel: +49 6221 387-8210
Fax: +49 6221
387-8518
E-mail: carsten.schultz@embl.de
Group home page
Dr. Marcus Mall
Group Leader
Department
of Pediatric Oncology, Haematology, Immunology and Pulmonology
Pediatric Pulmonology and Cystic Fibrosis Center
Children's Hospital, University of Heidelberg
Im Neuenheimer Feld 153
69120 Heidelberg
and
Otto-Meyerhof-Zentrum [Laboratory]
Im Neuenheimer Feld 350
69120 Heidelberg
Tel: +49 6221 568-840
Fax: +49 6221 568-806
E-mail: marcus.mall@med.uni-heidelberg.de
Website
Group Members
Amanda Cobos [PhD Student]
Bjarki Johannesson [PhD Student]
Link to Children's Hospital, University of Heidelberg |
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