G Protein Signaling in Brain Injury

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Traumatic brain injury (TBI) is a major cause of morbidity and mortality and affects >1.7 million people annually in the United States. Long-term TBI-related disability results in reduced quality of life for the patient and prolonged medical, social, and economic effects on society. TBI is a heterogeneous disease, encompassing both localized regions of necrotic neuron death, driven by oxidative damage and excitotoxicity, persistent tissue inflammation, and both progressive axonal injury and cerebral glucose hypometabolism. However, the mechanism(s) that initiate these diverse injury programs remains a critical knowledge gap, and a barrier to the development of effective TBI treatments. Remarkably, work in our lab now identifies the neuron-specific G-protein, RIT2 (Rin), as a regulator of neurodegeneration following brain injury. Exciting preliminary data demonstrates that RIT2 GTPase silencing significantly blunts in vivo hippocampal neuron death, attenuates behavioral dysfunction, and regulates the expression of the injury-activated SARM1 NADase following TBI. In keeping with a role for RIT2 in promoting neurodegeneration, expression of constitutively active RIT2 promotes energy collapse and neuronal death. Moreover, innovative metabolic studies identify a role for RIT2 in the regulation of cerebral glucose metabolism, suggesting that RIT2 contributes to the metabolic dysfunction seen following CCI. These data motivate the central hypotheses that: (1) RIT2 regulated signaling cascades contribute to the neuronal loss, metabolic, and neurobehavioral dysfunction seen following brain trauma, and (2) that inhibition of RIT2 signaling will therefore have broad therapeutic potential in the setting of TBI. Three complementary aims guide our studies. Aim1 will evaluate the extent to which RIT2 signaling controls neuronal loss and behavorial dysfunction following contusive brain injury. Aim 2 will employee innovative transcriptomic approaches to explore RIT2- and TBI-dependent alterations in neuronal gene expression, define the molecular basis of RIT2-SARM1 signaling, and explore the role for RIT2 in traumatic axonal injury. Finally, studies in Aim 3 will leverage state-of-the-art metabolic approaches to define the role for RIT2 in the regulation of neuronal metabolism following TBI. Together, this innovative, multi-system approach will generate insights into the molecular mechanisms that orchestrate neuronal dysfunction following brain contusion, and test the therapeutic potential of targeting RIT2 and its signaling partners for the treatment of TBI.