Inhibition of Rin GTPase Signaling Reduces Neurodegeneration andAttenuates Axonal Injury following Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and permanent disability in the United States, with TBI being a contributing factor to a third of all injury-related deaths. 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. Mechanisms of brain damage underlying focal contusion are 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 novel signaling pathways that promote acute neuron survival and limit axonal injury following TBI, with the hypothesis that manipulation of these pathways will have broad therapeutic potential. Our preliminary data indicates that Rin GTPase directed signaling plays a unique and critical role in functional recovery following TBI. First, Rin deficiency promotes cell survival, including activation of the Akt pathway, to reduce neurodegeneration and cognitive dysfunction after contusion TBI. Second, loss of Rin attenuates axonal degeneration and improves cognition after diffuse mild TBI. These data motivate the central hypothesis that: (1) Rin signaling plays a central role in cellular and functional recovery over a spectrum from mild to severe brain trauma, and (2) that inhibition of Rin signaling will therefore have broad therapeutic potential in the setting of TBI. Using clinically-relevant mouse models of contusive brain injury and diffuse mTBI, we will evaluate our hypothesis using three specific aims. Aim 1 will use Rin-/- mice to determine whether Rin deficiency protects against contusive TBI by reducing neuron death and improving cognitive function, in part via modulation of a novel Akt signaling pathway. Aim 2 will examine whether Rin loss protects against axonal injury, to lessen neurobehavioral dysfunction following repeated mTBI. Aim 3 will develop a new mouse model to allow acute adult Rin knockdown to explore the efficacy of Rin-targeted TBI therapies. This innovative, multi-system approach will generate insights into the molecular mechanisms of recovery, and may lead to novel strategies to rescue neurons and limit axonal damage after brain trauma. PUBLIC HEALTH RELEVANCE: Traumatic brain injury is a significant health concern, annually affecting ~2.5 million Americans at a cost of $76 billion (2010 data). The staggering societal and economic toll of brain injury highlights the need for new therapeutic agents designed to ameliorate the pathologies associated with TBI. The insights gained from the proposed experiments, and their potential for identifying novel therapeutic targets, will clearly benefit the search for such agents.