Visual Universitätsmedizin Mainz

Cell and Redox Signaling

 

Cell and redox signaling

 

Generation of reactive oxygen species (ROS) establishes a prime mechanism in signal transmission and is centrally involved in e.g. inflammation, development, defense of the infected host and those pathways that govern the balance between survival and cell death. Given this role, it is not surprising that redox signaling is intimately linked to leading causes of human death, such as cardiovascular or neurodegenerative diseases and cancer. Importantly, ROS are both signaling molecules and damaging entities. Thus, neither excessive production nor eradication of ROS remains without consequences.

Main ROS-producing enzymes are NADPH oxidases, xanthine oxidases, mitochondria and uncoupled eNOS. These are opposed by antioxidant enzymes such as SOD, catalase, GPx, HO, thioredoxin and paraoxonases (for further reading: Li / Horke / Förstermann, TiPS 2013). Among the latter, the paraoxonases PON2 and PON3 are a major focus of our lab and we investigate their regulation, mechanism and function in different in vitro and in vivo systems. Intriguingly, PON2 has two independent functions: (1) as part of the innate immune system, PON2 enzymatically inactivates specific bacterial virulence factors. This appears to be particularly important in Pseudomonas aeruginosa infections of cystic fibrosis patients. (2) it diminishes mitochondrial ROS and increases cell stress tolerance, which links it to e.g. cardiovascular diseases and cancer.

Among other functions, PON2 grants robust anti-oxidative and anti-apoptotic benefit to tumor cells due to enhanced evasion from cell death and resistance to chemotherapeutics. These findings and the known impact of redox signaling on quiescence, apoptosis, differentiation and self-renewal of hematopoietic stem cells (HSCs) prompted us to analyze the role of PON2 in HSC biology and differentiation.

In another project we plan to resolve the specific functions of PON2 in platelet activation and thrombosis as well as NOX2/PON2contributions to platelet redox homeostasis, calcium signaling, secretion and aggregation. Redox mechanisms significantly contribute to a pro-thrombotic state, because enhanced formation of reactive oxygen species (ROS) provokes an inflammatory milieu. This drives activation of endothelial cells and platelets, favors their interaction and facilities atherothrombosis.

Collectively, our mission is to understand the role of PONs in cancer (specifically in leukemias) and cardiovascular diseases (coagulation; atherosclerosis)

 

 

Methods used in our lab

We apply a broad range of standard and specific techniques, including cloning, Western blotting, real-time qRT-PCR, gene reporter analyses, FACS, live cell imaging, laser scanning microscopy, animal + (primary) cell culture studies, profiler arrays, cell viability studies, ROS detection, siRNA + vector transfection, bone marrow transplantation assays etc. Other sophisticated approaches are implemented in our esteemed collaborations.

 

 

Affiliation

Our research project, regarding the function of PON2 in platelets, as well as Victoria Petermann are officially affiliated with the Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz (link to the CTH).

Funding

Work in our lab is financially supported by the intramural funding programm of the University Medical Center Mainz / the JGU Mainz, by the Centre for Thrombosis and Hemostasis (CTH) Mainz and the German Research Foundation DFG

Awards & Activities

Sebastian Altenhöfer (2008)
Elected member of the Gutenberg Academy
[read more]

Sven Horke (2008)
Research Award
Robert-Müller Foundation
[read more]

Maximilian Krüger (2010)
Distinguished final thesis
Faculty of Medicine / JGU Mainz
[read more]

Eva-Maria Schweikert (2010 / 2011)
Supportive Stipend
University Medical Center Mainz

Sven Horke (2011)
Research Award
Boehringer-Ingelheim Foundation
[read more]

Julianna Amort (2011)
EMBO short-term fellowship
For studies at the VIB, Ghent, Belgium

Sven Horke (2011)
Member, Executive Committee of the Gutenberg Research College; the GRC is dedicated to the advancement of innovative research and interdisciplinary integration between research areas of excellence.
[Read more about the GRC]

Sven Horke (2013)
Approval of Translational Research Project TRP-A11i at the CTH Mainz
[Read more] 

Sven Horke (2013)
Co-founder of the Junior Group Leader Network JUGGLE at the Johannes Gutenberg University and its University Medical Center
[Read more about JUGGLE]

Sven Horke // Ines Witte (2014)
200.000 € Funding, Gerhard & Martha Röttger Foundation
[Read more]

Sven Horke (2014)
Elected appointee for the Gutenberg Research College Network
[Read more about the GRC]

Julia Ebert (2014)
CTH doctoral candidate fellowship

Sven Horke (2014)
Member of the Gutenberg Council for Young Researchers (GNK); the GNK is dedicated to the development of strategic perspectives and to the advancement of ideas and measures for their realization.
[Read more about the GNK]