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Somatisch erworbene Mitochondrienläsionen bei idiopathischer und Sklerodermie-assoziierter Lungenfibrose
| Third-party funded project |
| Project title |
Somatisch erworbene Mitochondrienläsionen bei idiopathischer und Sklerodermie-assoziierter Lungenfibrose |
| Principal Investigator(s) |
Walker, Ulrich A.
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| Co-Investigator(s) |
Roth-Chiarello, Michael
Tamm, Michael
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| Organisation / Research unit |
Bereich Medizinische Fächer (Klinik) / Rheumatologie FPS (Tyndall) |
| Project start |
01.07.2011 |
| Probable end |
30.06.2015 |
| Status |
Completed |
| Abstract |
Scleroderma (also called systemic sclerosis, SSc) and idiopathic interstitial lung
fibrosis are rare diseases with a very high mortality; in fact interstitial lung
involvement is the most frequent cause of death in SSc. Progressive fibrosis of the lung
is the hallmark of both diseases and results from an excess synthesis and deposition
of collagen. The etiology of the fibrosis in these conditions is poorly understood.
Despite some evidence for an involvement of the immune system, the pulmonary
collagen deposits are rarely amenable to immunosuppressive therapy in clinical
practice. There is now mounting evidence for an important role of reactive oxygen
species (ROS) which may perpetuate the fibrotic process in response to an unidentified
chronic injury.
In this grant proposal we aim to investigate the role of somatically acquired lesions in
mitochondria as perpetuators of the frequently relentless disease process.
Mitochondria are on the one hand the main cellular producers of ROS and on the
other hand themselves subject to oxidative injury of their genome (e.g. mitochondrial
DNA, mtDNA), lipids and protein structures. We specifically propose to investigate the
hypothesis that mitochondrial injury accumulates with time during the disease
process and contributes to, or may even be the main driver of ROS production and
subsequent fibrosis. Our hypothesis hinges on the fact that mtDNA damage leads to
respiratory chain dysfunction, a fact which subsequently generates even more free
radicals which then either attack the respiratory chain itself, or in turn damage
mtDNA. ROS may therefore close vicious circles composed of interconnected mtDNA
and respiratory chain insults. Such vicious circles may continue to operate even in the
absence of the inciting event of lung fibrosis and therefore account for its relentless
progression.
We will investigate this hypothesis by quantifying mtDNA mutation loads in a host of
well characterized human lung biopsies and in the bleomycin model of lung fibrosis.
We will then relate mutation loads to markers of pulmonary ROS production,
respiratory chain function, as well as disease characteristics (fibrosis type, severity,
and duration). We finally aim to demonstrate the direct pathogenetic relevance of
mitochondrial dysfunction by establishing fibroblasts devoid of a single molecule of
mtDNA (termed ?rho0´ fibroblasts) and by investigating the fibrotic phenotype of rho0
fibroblasts in vitro in terms of TGF-â release and collagen synthesis. We will also
differentiate mitochondrial from nuclear effects in healthy and diseased individuals by
examining the fibrotic potential of rho0 fibroblasts in comparison with fibroblasts
harbouring wild-type mtDNA.
Our new insights into the pathogenesis of lung fibrosis will help in the understanding
of lung fibrosis and the rational development of antifibrotic drugs. |
| Financed by |
Swiss National Science Foundation (SNSF)
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10/05/2024
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