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)