Simmons Conference: Drew Sayce, MD, PhD

Drew Sayce, MD, PhD

Title: The Unfolded Protein Response in Trauma and Sepsis

Description:

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 cohorts of critically-ill patients with sepsis (MARS consortium) in comparison to traumatically injured patients. Using single cell RNA sequencing, we define the time and cell-specific responses to trauma including a novel myeloid signature of UPR pathway switching in the first 24 hours of injury. Finally, we compare organ-specific glycan signatures as they develop over early time points of in murine models of sepsis and trauma. These studies form a foundation for understanding the time and cell specific UPR activation in critical illness. 

Mentors: Drs. Billiar, Zitzmann & Rosengart