Saturday, November 26, 2022
11/26/2022
Traumatic brain injury (TBI) is a major cause of death and permanent disability in the United States affecting more than 1.7 million individuals each year. TBI not only results in tissue damage and cell death, but can perturb surviving neuronal function, leading to alterations in neural connectivity, abnormal plasticity, and network dysfunction. Due to the inherent diversity in post-TBI dysfunction, a critical need exists for therapeutic interventions that target multiple injury mechanisms. Development of such multi-prong therapeutic approaches could have enormous clinical, social, and economic benefit. However, implementation of this strategy requires the identification of endogenous molecular cascades capable of regulating multiple protective/restorative pathways. The discovery that the Rit GTPase (RIT1) is dramatically down-regulated following cortical contusion injury (CCI) prompted studies to explore the contribution of Rit-directed signaling to functional recovery following TBI. Drawing upon a collection of RIT1 transgenic mice, exciting preliminary data demonstrate that Rit activation reduces in vivo neurodegeneration and alleviates cognitive dysfunction following CCI. Additional data suggest that Rit is critical for post-TBI neurogenesis and promotes synaptic integrity by reducing post-contusion synaptic loss. Collectively these data are the first to demonstrate a significant role for Rit in directing neuroprotection and neuroplasticity following TBI, and suggest that Rit functions as a linchpin regulator of multiple injury response mechanisms following CCI. The overall hypothesis is that: (1) Rit plays a key role in cellular and functional recovery from brain trauma, and (2) that activation of Rit signaling therefore has broad therapeutic potential in the setting of TBI. Three complementary aims guide our studies. Aim 1 will test the hypothesis that contusion-dependent Rit loss disrupts gene expression programs that promote neural survival and neurogenesis. In Aim 2 we will evaluate the extent to which Rit signaling controls neuronal survival after contusive brain injury. The efficacy of Rit-targeted therapies will be evaluated using an inducible knock-in mouse model to permit Rit activation over a clinically relevant period of hours to days after the onset of brain injury. Aim 3 will test the hypothesis that Rit signaling preserves synaptic function following traumatic brain injury using transgenic mice, electrophysiology, and biochemical assays. Overall, these studies are expected 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 neuroplasticity mechanisms.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
