RIT1-Mediated Protection Following Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and permanent disability in the United States affecting 3 more than 1.7 million individuals each year. TBI not only results in tissue damage and cell death, but can 4 perturb surviving neuronal function, leading to alterations in neural connectivity, abnormal plasticity, and 5 network dysfunction. Due to the inherent diversity in post-TBI dysfunction, a critical need exists for therapeutic 6 interventions that target multiple injury mechanisms. Development of such multi-prong therapeutic approaches 7 could have enormous clinical, social, and economic benefit. However, implementation of this strategy requires 8 the identification of endogenous molecular cascades capable of regulating multiple protective/restorative 9 pathways. Our discovery that the Rit GTPase (RIT1) is dramatically down-regulated following cortical contusion 10 injury (CCI) prompted studies to explore the contribution of Rit-directed signaling to functional recovery 11 following TBI. Drawing upon our collection of RIT1 transgenic mice, exciting preliminary data demonstrate that 12 Rit activation reduces in vivo neurodegeneration and alleviates cognitive dysfunction following CCI. Additional 13 data suggest that Rit is critical for post-TBI neurogenesis and find promotes synaptic integrity by reducing post-14 contusion synaptic loss. Collectively these data are the first to demonstrate a significant role for Rit in directing 15 neuroprotection and neuroplasticity following TBI, and suggest that Rit functions as a linchpin regulator of 16 multiple injury response mechanisms following CCI. Our overall hypothesis is that: (1) Rit plays a key role in 17 cellular and functional recovery from brain trauma, and (2) that activation of Rit signaling therefore has broad 18 therapeutic potential in the setting of TBI. Four complementary aims guide our studies. First, we will test the 19 hypothesis that contusion-dependent Rit loss disrupts gene expression programs that promote neural survival 20 and neurogenesis. Second, using our one-of-a-kind collection of transgenic mice, we will determine the extent 21 to which Rit activation protects against, and Rit loss exacerbates neurodegeneration and cognitive dysfunction 22 following contusive brain injury. Additional studies will explore the efficacy of Rit-targeted therapies using an 23 inducible knock-in mouse model to permit Rit activation over a clinically relevant period of hours to days after 24 the onset of brain injury. Third, using transgenic mice, electrophysiology, and biochemical assays, we will 25 determine the ability of Rit signaling to reduce synaptic loss and facilitate the recovery of synaptic strength 26 following brain injury. Our fourth aim focuses on our finding that Rit expression can drive reprogramming of 27 resident glia to proliferative neuroblasts in the cortex, offering the possibility of regenerative therapy following 28 TBI. An innovative mouse model, coupled with glia-directed viral expression, will be used to explore the 29 potential for Rit-mediated generation of induced neurons with the long term goal of post-CCI cortical repair. 30 Overall, we expect to identify Rit as a crucial signal integration hub in the setting of brain injury – orchestrating diverse endogenous pathways that regulate neuronal survival, promote neuronal regeneration, and control 32 neuroplasticity mechanisms. Project Narrative Traumatic brain injury (TBI) is a leading cause of death and disability in the 37 United States, often resulting in persistent cognitive deficits for which there are no effective treatments. This 38 proposal aims to investigate Rit signaling as a novel molecular mechanism underlying neuronal survival and 39 the generation of new neurons in the hippocampus following TBI. Understanding mechanisms that foster 40 hippocampal neuronal recovery is of fundamental importance to the development of cognitive treatment 41 strategies. 42