The Role of Platelets in Trauma-induced Organ failure

Organ failure occurs frequently after major trauma, but the cause is unknown and there are no specific treatments. I hypothesise that platelets drive a dysregulated immune response to major tissue injury, forming a fundamental but previously unidentified link between damage and secondary organ failure. I have previously described a range of profound changes in platelet phenotype and function after major trauma, including formation of highly activated platelet subsets, widespread platelet-leukocyte interactions, and increased circulating immature platelets. My aim is to decipher the mechanisms that link altered platelet activity to systemic inflammation and organ dysfunction after major trauma. I will address this through three interlinked objectives: Firstly, define how platelets modulate the behaviour of innate leukocytes, and the consequences for systemic inflammation. Secondly, understand the immunological properties of ballooning platelets, a highly activated subset we have previously identified in injured patients. Thirdly, determine the role of megakaryocytes and immature platelets in the innate response to injury. To deliver on these objectives, I will employ an integrated experimental plan with state-of-the-art methodologies incorporating patient samples and biologically relevant modelling techniques. These ambitious investigations, if successful, will have major impact upon our fundamental understanding of platelet biology and the innate response to injury.