# RIT1-mediated Protection following Traumatic Brain Injury

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $508,999

## Abstract

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.

## Key facts

- **NIH application ID:** 9864109
- **Project number:** 5R01NS102196-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Douglas Allen Andres
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,999
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864109

## Citation

> US National Institutes of Health, RePORTER application 9864109, RIT1-mediated Protection following Traumatic Brain Injury (5R01NS102196-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9864109. Licensed CC0.

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