Grants and Contracts Details
Description
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 cognitive
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 upregulates SARM1 to
promote NAD+ collapse and in vitro neuronal loss. 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 cognitive 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 cognitive 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.
Status | Active |
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Effective start/end date | 7/1/22 → 6/30/25 |
Funding
- National Institute of Neurological Disorders & Stroke: $535,500.00
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