Dr. Andrew Sayce presents "The Unfolded Protein Response in Trauma and Sepsis"

Dr. Andrew Sayce, MD DPhil

Title: The Unfolded Protein Response in Trauma and Sepsis

Inflammatory signaling in response to traumatic injury, hemorrhagic shock, and surgical sepsis has been extensively studied. Similarly detailed exploration of the endoplasmic reticulum (ER) stress response has uncovered the mechanisms by which cells recognize and respond to accumulation of unfolded and misfolded proteins, the unfolded protein response (UPR). Trauma and surgical sepsis (i.e., infections requiring surgical management to control the septic source) induce states of profound cellular stress requiring widespread transcriptional and translational reprogramming, and the secretory demands imposed at these times can easily overwhelm the protein processing capacity of the ER and trigger the UPR.

We are investigating the UPR in trauma and sepsis through a systematic approach involving transcriptomic, proteomic, and glycomic techniques. We present an analysis of the largest published cohort of critically-ill patients with sepsis (MARS consortium) with a specific focus on the role of the UPR in molecular and clinical phenotypes. Previously defined endotypes (Mars1-4) demonstrate marked differences in UPR activation within the first 24 hours of admission to the ICU. Over-activation of PERK signaling, one of the three principle arms of the UPR, is robustly associated with mortality.

Mentors: Drs Mattew Rosengart, Tim Billiar, Zitzmann