Grant: Collaborative Research and Development Grants

Iron has different functions in living beings. On one hand it is required as an irreplaceable trace element by all cells. On the other hand, free iron is toxic and can be involved in cellular destruction. This complex interplay is of particular interest for example in immune cell function. Iron scavenging agents (chelators) are able to modulate the response of the immune system to triggers like inflammation or infection. However, a better understanding of the discrete roles that iron and its sequestration by chelators plays at the basic cellular level is needed. Chelation Partners Inc. (CP), our Industrial Partner, has developed a family of novel iron chelators. The availability of those highly-specific iron scavenging substances makes it possible for the first time to investigate the different roles that iron plays in cellular pathways in vitro. Such studies also require appropriate whole animal experiments to confirm the iron-related mechanisms in the complete organism. We have established whole animal model systems and in vivo methods to study the differential roles of iron and its sequestration in both inflammation and infection. The focus of the research in the inflammatory models (from sterile infection-free inducers, e.g. lipopolysaccharide) is the study of iron-related processes, e.g. reactive oxygen species generation, and the impact of iron removal on immune cell function. These responses will be compared to a polymicrobial infection model caused from natural gut flora (peritonitis-induced sepsis) and here we will attempt to elucidate the combined microbial inflammation signaling and response to infection on top of the underlying inflammatory processes.