The overall objective of our research includes the study of cellular processes that are responsible for the controlled regulation of inflammation in heart muscle diseases. Our group is interested in the importance of the myocardial cell as a central point of an immune response, for example, during infection with pathogens. We examine the significance of a regulation of the cellular protein equilibrium by the ubiquitin-proteasome system and by the ubiquitin-like modification ISG15 in various pathological conditions in the heart muscle. These regulatory principles are examined in particular at the interface between innate and adaptive immunity for their relevance to translational issues.
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Relevance of the exploratory focus
For a controlled immune response, also called immune homeostasis, an adaptation of cellular protein degradation by the ubiquitin-proteasome system is of central importance. In this concert of controlled protein degradation during inflammation, proteins are not only modified with ubiquitin but also with the ubiquitin-like modifier ISG15 – a process called ISGylation. Both protein modification systems - ubiquitylation and ISGylation – are not occurring independently but rather influence each other. My working group could work out the central role of these cellular systems during a viral myocarditis.
Our understanding of these systems in myocarditis/inflammatory cardiomyopathy are highly relevant to clinical practice. Especially with this pathophysiological condition there is a high need for innovative therapies. It lacks specific therapeutic principles targeting pathogens specifically in cardiac muscle cells and then again control the immune response in favor of the host. Due to the significance of this scientific field for the fundamental understanding of the pathogenesis of inflammatory myocardial diseases and socio-economic relevance of these diseases, our research can considerably contribute to the identification of causal therapies.
(A) ISG15/ISGylation: Regulator of intrinsic immune defense in cardiomyocytes
A major focus of my research group relates to the characterization of the interferon-stimulated genes of function 15 kDa (ISG15). As part of the DFG priority program 1365 "ubiquitin-family proteins" my lab has worked out the ISG15 system as a central mechanism of myocardial cell-specific intrinsic immune response. We are interested in the molecular mechanisms how the ISG15 system changes the proteome in heart muscle cells in order protect cells against pathogens, for example. Based on these findings we are currently developing gene therapeutic approaches that allow the analysis of the medical benefit of this system in inflammatory cardiomyopathies.
Funding: DFG VO 1602/5-1 (2014-2017), Hengstberger-Forschungsstipendium (2015-2017)
Involved lab members: Martin Voß, Meike Kespohl, Anika Lindner, Martin Zickler
(B) Regulation of inflammatory cardiomyopathy by the ubiquitin-proteasome system
The outstanding homeostatic and pathophysiological significance of the ubiquitin-proteasome system is indisputable today. The second focus of my research activity is the functional importance of specific proteasome isoforms and proteasome regulators, which are specifically expressed in immune cells before pathogen contact. In our studies we investigate how these certain isoforms of the proteasome influence the function of immune cells at a given genetic predisposition, and thus have an impact on the course of a disease. In addition to the molecular mechanisms underlying the regulation of the immune response by these immune cell-specific proteasome isoforms, my lab is interested in the relevance of these components of the proteasome as "drug targets" during the various stages of an inflammation of the heart muscle. The immunomodulatory constituent of such a therapeutic approach may be useful for serious viral infections and resulting autoimmune diseases and other cardiovascular inflammatory processes such as atherosclerosis.
Funding: Hofschneider Stiftungsprofessur (2016-2020), DFG VO 1602/4-1, DZHK (mit Prof. Dr. med. Ziya Kaya – Heidelberg), BIH MD Stipendium, DFG 1602/2-1 mit Prof. Dr. Elke Krüger (Institut für Biochemie, Charité – Universitätsmedizin Berlin)
Involved lab members: Nadine Althof, Carl-Christoph Goetzke, Dorota Respondek, Karolin Voß