# G Protein Signaling in Brain Injury

> **NIH NIH R56** · UNIVERSITY OF KENTUCKY · 2022 · $535,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10626681
- **Project number:** 1R56NS124707-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Douglas Allen Andres
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $535,500
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10626681

## Citation

> US National Institutes of Health, RePORTER application 10626681, G Protein Signaling in Brain Injury (1R56NS124707-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10626681. Licensed CC0.

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