In the past years we have been investigating the role of C/EBP homologous protein (CHOP) in the pathogenesis of sepsis. This transcription factor is a mediator of the endoplasmic reticulum (ER) stress response. The ER is crucial for cell survival because this is the site of post- translational modifications, folding, and assembly of newly synthesized proteins. Many lines of evidence suggest a cross-talk between the inflammatory response and the ER-stress response, and the latter has been implicated in several, important human pathologies such as obesity, diabetes type 2, atherosclerosis and neurodegenerative disorders. In some instances, accumulation of unfolded proteins leads to ER stress. This stress response, called the ?unfolded- protein response? (UPR) protects cells from various insults and is important to homeostasis. CHOP is one of the important mediators of the ER stress response and known to be a pro- apoptotic modulator. However, recent evidence indicates that CHOP may also play an important role during inflammation, suggesting that it is not only involved in apoptosis. Using CHOP KO mice we show for the first time that these mice display a significantly increased survival after polymicrobial sepsis or endotoxemia compared to WT mice. The inflammatory response, and apoptosis in the spleen in these mice, is highly reduced while bacterial clearance in the blood and peritoneum cavity augmented. Thus, our study demonstrated a crucial and unacknowledged role for this transcription factor in dictating survival. These new and exciting findings brought us to our hypothesis that CHOP is a novel determinant of survival during sepsis The overall goal of this exploratory application is to gain preliminary insight on the mechanism(s) by which Chop deletion leads to a significant increase in survival in mice. We show that CHOP is directly linked to survival, although the mechanisms are unknown. In this application we will investigate the role that CHOP plays in aim #1) leukocyte recruiting and trafficking, aim #2) macrophages polarization and function, and aim #3) splenic marginal zone role in survival. These studies will significantly increase our knowledge and understanding of the mechanisms involved in the innate immune response during sepsis. Since severe sepsis and septic shock remain a leading cause of death in the intensive care unit, with over 210,000 annual deaths in the United States, identification of new molecular targets to improve survival from this syndrome, if successful, could have a major public health benefit.
The over-all goal of this proposal is to gain insight into the mechanisms of sepsis induced mortality. We will investigate the new role of the transcription factor CHOP in the innate immune response, elucidating different aspects of leukocyte biology and regulation of inflammatory mediators during sepsis.
