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German Federal Ministry of Defense research project M/SABX/BA003

Innovative therapeutic strategies in the treatment of sulfur mustard-affected skin: modulation of HIF 1α signaling and microRNA regulated pathways.

 

Its relative ease of production and stockpiling together with its multiple incapacitating health effects make mustard gas a continuing threat. Identification of effective therapies for SM-induced injuries is the focus of research worldwide.

The results of our previous research projects supported by the German Federal Ministry of Defense in 2005-2011 (M/SAB1/A001 and M/SABX/8A002) provided for the first time insight into molecular and cellular mechanisms that may contribute to the pathogenesis of SM injury. Our in vitro studies demonstrated that SM upregulates the release of proteinases from various skin cells. Remarkably, SM exposure of keratinocytes was shown to trigger the release of soluble factors from the cells which then induce an enhanced secretion of matrix metalloproteinase 9 (MMP-9) from fibroblasts. This may represent a SM-mediated pathomechanism that can lead to an increased degradation of basement membranes and thereby facilitate blister formation in skin (Ries C. et al., Toxicology, 2009). Moreover, our findings indicated that SM triggers premature differentiation in keratinocytes via p38 MAP kinase activity which is negatively influenced by ERK1/2. These events may contribute to the impaired regeneration capacity of skin after exposure to SM (Popp T. et al., Toxicology Letters, 2011). Together, our results suggest the usefulness of MMP-9 and p38 MAP kinase-inhibitors when applied in a timely differentiated manner for the treatment of SM-induced acute and chronic symptoms.

In a further project (M/SABX/8A002) we currently investigate the importance of oxygen-deficiency (hypoxia), especially the role of HIF-1α and microRNAs in the pathophysiology of SM. Under normal physiological conditions, wound-associated hypoxia is a timely-limited situation that acts as an important stimulus for proper healing and regeneration in skin. Hypoxia controls the function and behaviour of keratinocytes and fibroblasts by influencing the expression of various regulatory molecules including cytokines and proteinases. In this context, HIF-1α plays a key role because it is significantly upregulated during hypoxic conditions in the skin and thereby stimulates various processes including cell proliferation, migration, autophagy, and angiogenesis that facilitate wound healing. We hypothesize, that SM causes dysregulation in HIF-1α-mediated signal transduction pathways which contributes to the pathophysiology of impaired tissue regeneration in SM-injured skin. The elucidation of SM-evoked malfunctions in keratinocytes and/or fibroblasts provoked by a disturbance of HIF-1α cell signaling would provide new therapeutical strategies of intervention including the application of specific agents that inhibit or stabilize HIF-1α activity.

Autophagy is a tightly regulated catabolic process important in cell growth and development. Under stress conditions such as nutrient deficiency, autophagy facilitates cell survival by degradation of subcellular components through the lysosomal machinery, or initiates controlled cell death (apoptosis). Our studies aim to explore whether SM exposure to skin cells interferes with the balance between survival and apoptosis in keratinocytes which may result in delayed wound healing.

microRNAs are a group of small non-coding RNA molecules that play key roles in the regulation of numerous physiological and pathological processes. In wound healing, microRNAs are involved in the control of inflammation, angiogenesis, and apoptosis especially by influencing the functions of keratinocytes and fibroblasts. Interestingly, specific microRNAs seem to be regulated by HIF-1α signaling. Therefore, a major part of our project aims to analyze the influence of SM on microRNA expression profiles in keratinocytes and fibroblasts. SM-mediated alterations in cellular microRNA signatures may indicate defects in the functions of these cells essential in normal wound healing. These findings could provide the opportunity for the development of innovative therapeutical concepts such as the topical application of microRNA inhibitors or microRNA agonists in the treatment of SM-injured skin.

 

Principal investigator: PD Dr. rer. nat. Christian Ries

 

Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten

Klinikum der Universität München, Ludwig-Maximilians-Universität München

Pettenkoferstrasse 9b, Raum 1304

D-80336 München, Germany

Tel.: 089-5160-5310

Fax: 089-5160-4740

Mail: christian.ries@med.uni-muenchen.de

 

 

 

 
 
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Direktor: Prof. Dr. med. Christian Weber

Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten (IPEK)

 

Pettenkoferstraße 8a & 9

80336 München

 

Tel.: 089-4400-54351

Fax: 089-4400-54352

Mail: Kreislaufinstitut@med.uni-muenchen.de

 

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