Natural self-reactive IgM antibodies represent a class of innate pattern recognition receptors that recognize danger associated molecular patterns (DAMPS) as neoepitopes expressed on stressed or dying cells. Recognition of these neoepitopes by IgM activates complement, initiating an inflammatory reaction, which can have injurious as well as protective effects. The overall goals of this project are to better characterie the innate immunogenic alterations that occur following ischemia and stress, to fully characterize the neoepitopes that serve as DAMPs, and to understand the complement activation event and complement effector mechanisms involved in the balance between sterile inflammation and injury on the one hand, and tissue repair/regeneration on the other. Complement inhibitors will be used in mouse models as therapeutically relevant investigative tools, and the focus of the studies will be on hepatic ischemia reperfusion injury and regeneration.
Ischemia/reperfusion injury (IRI) is a major clinical problem associated with clinical conditions involving vascular occlusion resulting from, for e.g., hemorrhagic shock, severe burns, sepsis, myocardial infarction, stroke and organ transplantation. The long-term goal of this project is to develop a therapeutic strategy to safely and effectively treat IRI and to promote tissue repair and recovery in order to improve outcome after various surgeries, including organ transplantation. These studies are focused on the liver.
