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Molecular Medicine Partnership UnitResearch Groups

Pathogenesis and treatment of cystic fibrosis

Carsten Schultz and Marcus Mall

Marcus Mall and Carsten Schultz

Project Summary

The focus of this project is on the pathogenesis and treatment of cystic fibrosis (CF) lung disease, one of the most common lethal hereditary diseases in Caucasians. We use an interdisciplinary approach combining chemical biology and in vivo analyses of genetically engineered mouse models to advance our current understanding of the pathogenesis, identify novel biomarkers and develop efficient therapeutic strategies for CF lung disease. The long term goal of this project is the translation of the results from pre-clinical models into the clinic.

Background

Marcus Mall has studied the basic ion transport defect in cystic fibrosis (CF) airways and developed a transgenic mouse model of CF lung disease. Carsten Schultz developed small molecule compounds that target the CF ion transport defect, and fluorescent sensors to monitor enzyme activities and intracellular signaling events in living cells. They joined the MMPU in 2006 to coordinate their longstanding research interests in cystic fibrosis.
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Goals

The overall goal of our interdisciplinary MMPU group is to combine our expertise in the generation and phenotypic characterization of genetically engineered mouse models of CF lung disease, the generation of small molecule compounds that target deficient epithelial signaling, and novel reporter molecules that can visualize disease processes in chronic lung disease in mice. With this interdisciplinary approach, we aim to gain a better understanding of the pathogenesis and pre-clinical development of more effective therapies for CF. The long term goal of this project is to identify novel biomarkers and treatment strategy for CF and potentially other chronic inflammatory lung diseases, and the translation of the results from pre-clinical models into the clinic.

Research Focus 1: Role of proteases in pulmonary inflammation and emphysema

Elevated activity of proteases leading to proteolytic damage of airways and alveolar structures has been implicated in the pathogenesis of pulmonary inflammation emphysema. In this project, we develop novel FRET probes to monitor protease activity in biological samples from a mouse model of cystic fibrosis (CF) lung disease and from CF patients. We will use these FRET probes to elucidate the role of proteases in disease pathogenesis and evaluate their role as biomarkers for CF and other chronic inflammatory lung diseases.
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Research Focus 2: Ion transport defect in cystic fibrosis airways

Defective regulation of airway ion transport and airway surface liquid (ASL) homeostasis causes impaired mucociliary clearance and plays an important role in the pathogenesis of cystic fibrosis (CF) lung disease. This project focuses on the mechanisms underlying the dysregulation of ion transport and ASL, and on the effect of small molecule compounds that target epithelial signalling to counteract the basic ion transport defects in native airway tissues. Successful approaches will be further evaluated for their therapeutic benefits in mouse models of CF lung disease.
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Selected Publications

Lack of neutrophil elastase reduces inflammation, mucus hypersecretion and emphysema, but not mucus obstruction, in mice with CF-like lung disease.
Gehrig S, Duerr J, Weitnauer M, Wagner CJ, Graeber SY, Schatterny J, Hirtz S, Belaaouaj A, Dalpke AH, Schultz C, Mall MA.
Am J Respir Crit Care Med. 2014 Mar 28. [Epub ahead of print]

FRET-based and other fluorescent proteinase probes.
Hu HY, Gehrig S, Reither G, Subramanian D, Mall MA, Plettenburg O, Schultz C.
Biotechnol J. 2014 Feb;9(2):266-81. doi: 10.1002/biot.201300201. Epub 2014 Jan 27.

CFTR Regulates Early Pathogenesis of Chronic Obstructive Lung Disease in βENaC-Overexpressing Mice.
Johannesson B, Hirtz S, Schatterny J, Schultz C, Mall MA.
PLoS One. 2012;7(8):e44059. Epub 2012 Aug 24

mCLCA3 does not contribute to calcium-activated chloride conductance in murine airways. Mundhenk L, Johannesson B, Anagnostopoulou P, Braun J, Bothe MK, Schultz C, Mall MA, Gruber AD.
Am J Respir Cell Mol Biol. 2012 Jul;47(1):87-93. Epub 2012 Feb 23.

Spatially resolved monitoring of neutrophil elastase activity with ratiometric fluorescent reporters.
Gehrig S, Mall MA, Schultz C.
Angew Chem Int Ed Engl. 2012 Jun 18;51(25):6258-61. doi: 10.1002/anie.201109226. Epub 2012 May 3.

The ßENaC-overexpressing mouse as a model of cystic fibrosis lung disease
Zhou Z, Duerr J, Johannesson B, Schubert SC, Treis D, Harm M, Graeber SY, Dalpke A, Schultz C, Mall MA
J Cyst Fibros. 2011 Jun;10 Suppl 2:S172-82.

Airway surface liquid volume regulation determines different airway phenotypes in liddle's compared to {beta}ENAC-overexpressing mice
Mall MA, Button B, Johannesson B, Zhou Z, Livraghi A, Caldwell RA, Schubert SC, Schultz C, O'Neal WK, Pradervand S, Hummler E, Rossier BC, Grubb BR, Boucher RC.
J Biol Chem. 2010 Jun 21

Reporters to monitor cellular MMP12 activity
Amanda Cobos-Correa, Marcus A. Mall, Carsten Schultz
Proc. SPIE  2010, Vol. 7576, 757605

Membrane-bound FRET probe visualizes MMP12 activity in pulmonary inflammation.
Cobos-Correa A, Trojanek JB, Diemer S, Mall MA, Schultz C.
Nat Chem Biol. 2009;5:628-30.  

 

Research group's link to University Hospital web page