Traumatic brain injury (TBI) affects over 1.4 million Americans each year. In 2008, the most recent year that complete statistics are available, 27,507 US military service members sustained a "mild or greater" TBI. This level of brain injury can have significant chronic or long-term effects. Long-term effects of TBI include difficulties in concentration and memory, balance and vision changes, sleep disturbances, and an increase in seizures. Edema (swelling) and inflammation (a response of the immune system to injury) are significant contributors to the underlying damage. One component of inflammation is the humoral Complement response, where Complement refers to a cascade of specific inflammatory proteins. High Complement levels may be related to poor neurological or brain function after TBI injury in humans. Despite clinical and animal model evidence documenting a role for inflammation in TBI, only corticosteroids have undergone clinical trials in TBI, resulting in recent calls for the testing and pursuit of more anti-inflammatory agents for this type of injury. Accordingly, this grant proposal seeks to investigate the role of Complement in TBI, using a unique inhibitor of Complement protein C1 (C1INH), which regulates vascular permeability (how well components of the blood stream can enter the brain) and inflammation (what components of the immune system are activated or suppressed). C1INH inactivates a variety of Complement cascade proteins, as well a proteases of the coagulation, contact, and fibrinolytic systems. C1INH has been tested extensively in other animal models of disease and injury where inflammation plays a role with promising results. For the present studies, we propose to use a recombinant human Complement component 1 (C1) esterase inhibitor (rhC1INH), the recombinant analogue of human C1 esterase inhibitor (C1INH). rhC1INH has been developed as a treatment for hereditary angioedema (HAE), a life-threatening disease resulting from genetic deficiencies in endogenous C1INH. The efficacy and safety of rhC1INH in treating HAE has been evaluated in eight clinical studies, including two randomized double-blind, placebo-controlled clinical trials. We believe that the experiments proposed here, which use Complement-sufficient animal models of TBI and rhC1INH to block multiple routes of Complement pathway activation, may provide new insight into the inflammatory mechanisms of TBI, and data that could permit the development of anti-inflammatory therapeutic strategies for TBI. This proposal is particularly promising because if positive evidence for rhC1INH improving function in a model of TBI is found in these studies, the pathway to a clinical trial in human is shorter than for a compound that has not already been tested in humans.