Trauma-hemorrhage is the most common cause of morbidity and mortality in immediate survivors of accidents, terrorist attacks, natural disasters, warfare casualties and medical emergencies. Injury accounts for 40% to 80% of total death for people between one to 37 years old in the USA. After injury, hemorrhage remains a major cause of death and is responsible for 30% to 40% mortalities;half of them die during the pre-hospital period. Despite significant advances in trauma care, the outcomes for trauma-hemorrhage patients have not significantly improved. The long-term goal of this study is to develop effective therapy to sustain life and enhance recovery of trauma-hemorrhagic patients. Hypothesis: Toll-like receptor (TLR)-mediated responses determine the outcomes of trauma-hemorrhage. The rationale for this hypothesis is based on our recent observations that mice which are deficient in TLR4 show attenuation of cardiac dysfunction in trauma-hemorrhage. In addition, we have reported that modulation of TLR signaling significantly reduces morbidity and mortality associated with septic shock. The specific aims are: Specific Aim 1: Define the mechanisms of TLR4-deficiency that prevent cardiac dysfunction after trauma-hemorrhage. The mouse model of trauma-hemorrhage established in our laboratory will be used for the study. Wild type and TLR4 knockout mice will be assigned to: control, sham operation, and trauma-hemorrhage groups. Specific pharmacologic agent that blocks the PI3k/Akt pathway will also be used to define the signaling pathways that are responsible for alterations of morbidity and mortality. TLR4 antagonist will be evaluated as a possible drug to treat trauma-hemorrhagic patients. Specific Aim 2: Determine the mechanisms of TLR2 activation that improve survival and enhance recovery after trauma-hemorrhage. The beneficial mechanisms of TLR2 agonist will be evaluated in our trauma-hemorrhage animal model. Involvement of the PI3K/Akt signaling pathway will be examined using its specific inhibitor. The optimal concentration of TLR4 antagonist and TLR2 agonist by themselves and in combination will be used as pre-hospital treatment applying to the simulated animal model. Both short-term and long-term outcomes will be followed. This project may lead to high impact publications and the development of novel and innovative strategies for preventing/managing cardiac dysfunction and enhancing recovery in traumahemorrhagic shock. PUBLIC HEALTH RELEVANCE: For the immediate survivors after an accident, terrorist attack, natural disaster, or warfare;the injury to tissue and bleeding are the most common cause of death. Despite many advances in taking care of these patients, the death rate is still unacceptably high. This study is to develop new and innovative treatments for the victims.