Sepsis continues to affect millions of people around the world, and the incidences are increasing. Sepsis is difficult to treat given the multi-factorial complications associated with this syndrome. The scientific literature that exists on sepsis and the amount of laboratories dedicated to its study indicate that there is still much to understand about the pathophysiology of this syndrome. Of particular interest to us are how the endogenous cell suicide program, i.e., programmed cell death, apoptosis, typically utilized to regulate regenerative and wound healing processes, are altered to contribute to morbid events that contribute to organ injury/damage. In this dissertation, I have sought to address the question; what role does Receptor Interacting Protein 1 (RIP1) (a regulatory kinase involved in cell death, pro-survival and/or inflammatory signaling) plays in the progression of septic liver injury? To do this, I utilized a murine model of sepsis to determine if RIP1 was involved in cell death signaling via Fas death receptor, initially, using the in vivo delivery of silencing RNA (siRNA) directed against RIP1. Surprisingly, these experiments document that RIP1 actually was required for septic rodent survival and not its morbidity. Subsequent work using a pharmacological inhibitor of the RIP1 kinase domain activation, Necrostatin 1 (Nec1), demonstrated that RIP1 is important for the animal's overall survival for sepsis. The kinase domain of RIP1 appears to be involved in NF kappa B pro-survival signaling. Our studies analyzing glycogen phosphorylase activity using Nec1 and RIP3, suggest that RIP1 appears to play a role in glucose metabolism in the liver (and not so much cell death via apoptosis/necrosis/necroptosis, which may account for some of the morbid changes seen in the septic mouse liver. Finally, we consider our observation on RIP1 made here relative to the literature, RIP1 potential as a therapeutic target and why this may be important in sepsis.
McNeal, Sam I.,
"The Role of RIP1 Kinase in the Progression of Septic Liver Injury"
(2013).
Pathobiology Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z0NZ85Z8
