Injuries are the third leading cause of death in the United States, and the number one cause in the younger population. Hemorrhagic shock is the leading cause of mortality and morbidity in trauma patients. Efforts to improve outcome are focused on early control of hemorrhage and adequate resuscitation. However, it is now being recognized that conventional resuscitation fluids might actually potentiate the cellular injury caused by hemorrhagic shock and increase apoptotic cell death. Development of more sophisticated strategies that can compliment (or replace) current resuscitation paradigms is an area of exciting new research. 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 gene expression and regulate downstream signal cascades and survival pathways. Histones are known regulators of gene expression, and pretreatment with histone deacetylase inhibitors (HDACI) has been shown 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 shock to improve survival and preserve organ viability, and to identify key cellular pathways that are involved in mediating this survival.
SPECIFIC AIM 1 - Determine whether administration of HDACI after the induction of hemorrhage would attenuate 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 cell survival pathways, using a combination of genomic and proteomic techniques.
Sub aim 1 : Determine whether the beneficial properties of HDACI are specifically due to its effects on histones.
Sub aim 2 : Identify the genes whose transcription is influenced by the administration of HDACI, and the changes in expression of proteins that make up the cell survival signaling pathways.
Sub aim 3 : Quantify the levels and function of apoptotic proteins in response to HDACI administration. Blood loss remains the major cause of death in trauma patients and our current methods of resuscitation are non-specific, often ineffective, and are associated with well-defined complications. Development of novel strategies, such as the use of drugs to improve the chances of survival, is an area of exciting new research and may lead to improved outcome in hemorrhagic shock. ? ? ?
