Small G-protein Signaling in Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and permanent disability in the United States (~2.5 million civilians sustained a TBI in 2010), with TBI being a contributing factor to a third of all injury-related deaths in the US. Long-term TBI-related disability results in reduced quality of life for the patient and prolonged medical, social, and economic effects on society. Current estimates suggest that approximately 3-5 million persons (1.1%-1.7% of the U.S. population) live with long-term disabilities that result from an injury to the brain. The annual economic cost of TBI in the US is estimated to be $76 billion (2010 data). Thus, the development of therapeutic approaches to treat TBI-mediated disorders is of enormous clinical, social, and economic benefit. TBI is a heterogeneous disease. Mechanisms of brain damage underlying focal contusion and diffuse concussive TBI overlap, but also have significant distinct features. Focal contusion is associated with localized regions of necrotic neuron death, driven by oxidative damage and excitotoxicity. In contrast, axonal injury and persistent tissue inflammation are thought to be major contributors to morbidity with diffuse mild TBI (mTBI). Due to the diversity of brain damage mechanisms that play a role in TBI, therapeutic interventions that target multiple mechanisms are likely to have a maximal impact for improving the quality of life of patients. The long-term objective of these studies is to understand molecular mechanisms that promote acute neuron survival and limit axonal injury and neuroinflammatory processes following TBI, with the hypothesis that manipulation of these pathways will have broad therapeutic potential.