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Somatisch erworbene Mitochondrienläsionen bei idiopathischer und Sklerodermie-assoziierter Lungenfibrose

Research Project
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01.07.2011
 - 30.06.2015

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.

Members (3)

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Ulrich A. Walker

Principal Investigator
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Michael Roth-Chiarello

Co-Investigator
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Michael Tamm

Co-Investigator