Injuries are the third leading cause of death in the United States, and the number one cause in the youngerpopulation. Hemorrhagic shock is the leading cause of mortality and morbidity in trauma patients. Efforts toimprove outcome are focused on early control of hemorrhage and adequate resuscitation. However, it isnow being recognized that conventional resuscitation fluids might actually potentiate the cellular injurycaused by hemorrhagic shock and increase apoptotic cell death. Development of more sophisticatedstrategies that can compliment (or replace) current resuscitation paradigms is an area of exciting newresearch. One such strategy is direct manipulation of gene transcription to help the cells endure ischemia-reperfusion injury, and to promote a pro-survival phenotype. Hemorrhage and resuscitation alter geneexpression and regulate downstream signal cascades and survival pathways. Histones are knownregulators of gene expression, and pretreatment with histone deacetylase inhibitors (HDACI) has beenshown to improve survival after lethal hemorrhage, through mechanisms that are not well defined.LONG TERM OBJECTIVE - Establish the effectiveness of HDACI in the setting of lethal hemorrhagic shockto improve survival and preserve organ viability, and to identify key cellular pathways that are involved inmediating this survival.
SPECIFIC AIM 1 - Determine whether administration of HDACI after the induction of hemorrhage wouldattenuate organ injury, and improve survival in a clinically relevant rodent model of hemorrhagic shock.
SPECIFIC AIM 2 - Determine whether the protective effects of HDACI are exerted through modulation of cellsurvival pathways, using a combination of genomic and proteomic techniques.
Sub aim 1 : Determinewhether the beneficial properties of HDACI are specifically due to its effects on histones.
Sub aim 2 : Identifythe genes whose transcription is influenced by the administration of HDACI, and the changes in expressionof proteins that make up the cell survival signaling pathways.
Sub aim 3 : Quantify the levels and function ofapoptotic proteins in response to HDACI administration.Blood loss remains the major cause of death in trauma patients and our current methods of resuscitation arenon-specific, often ineffective, and are associated with well-defined complications. Development of novelstrategies, such as the use of drugs to improve the chances of survival, is an area of exciting new researchand may lead to improved outcome in hemorrhagic shock.
