Targeting necrotic cell debris degradation as a therapeutic strategy for injury

Injury is inevitable in multicellular organisms. Our bodies are frequently injured by extreme temperatures, mechanical damage and chemical toxicity, causing a form of cell death named necrosis. Necrotic cell death is highly proinflammatory and drives disorders such as liver injury, severe trauma and burn injuries. This harmful effect depends on the cell debris that is left behind, but there is little understanding on how organisms deal with necrotic remnants. Our main objective is to elucidate a vital, yet neglected process: the clearance of necrotic cell debris. We hypothesize that three of the most abundant debris - DNA, histones and actin - act together in a vicious cycle that inhibits the degradation of one another. When found in complexes in necrotic injuries, they may prevent the activity of serum DNAses. Importantly, this clearance mechanism is likely independent of infiltrating inflammatory leukocytes. We will investigate the immunological and biochemical properties of debris released during injury using my unique expertise in intravital microscopy and clinically-relevant disease models. We will determine the physiological relevance of local and systemic necrotic debris clearance, with focus on nucleosomes and actin. Moreover, we will synthesize novel peptides to disassemble necrotic debris and accelerate its clearance at any phase of injury. This project will expand our understanding of the response to injury and pave the way for new therapies for acute injuries.