Presentation description

One in three people who die in a hospital had sepsis during their hospitalization according to data reported by the CDC. Sepsis is a life-threatening condition caused by a disproportionate immune response during infection. Patients that are at higher risk include the elderly and those with chronic medical conditions such as diabetes, cancer, or kidney disease. As part of this disproportionate immune response, platelets circulating throughout the body secrete a variety of molecules involved in signaling and promoting a clot; excessive clotting during conditions of sepsis may lead to multiple organ failure and oftentimes loss of life. The complete mechanism of how sepsis causes increased platelet granule secretion is not fully understood but is under investigation in this project. Ongoing work in the Rondina lab has identified a sepsis-induced molecular switch that regulates platelet granule secretion called Interferon-induced transmembrane protein 3 (IFITM3). Data suggests that inflammation-induced increase in IFITM3 in platelets is associated with increased granule secretion. Release of molecules from platelet compartments or granules, is mediated by a class of proteins called Soluble N-ethylmaleimide Factor Attachment Receptor Proteins (SNARE). Loss of one or more SNAREs caused reduced granule secretion. Chief among these is the Vesicle-Associated Membrane Protein 8 (VAMP-8), Syntaxin-11, and SNAP-23, which are essential in mediating platelet secretion. The purpose of this project is to investigate whether under inflammatory conditions, IFITM3 mediates platelet granule secretion by interacting with these SNARE molecules. The hypothesis is currently being tested using a CRISPR Cas9 system to knock out genes involved in the exocytosis of platelet granule contents and investigating the effects of this knockout on the platelet granule secretion. Gaining a better understanding of the mechanism of platelet granule secretion would expand our knowledge of why blood clotting occurs during inflammatory conditions such as sepsis.