For decades, there has been a critical gap in translating preclinical work on mechanisms of cerebral edema in
traumatic brain injury (TBI) to clinically available targeted therapies that improve outcome. This is important
because cerebral edema management commands substantial clinical and financial resources in severe TBI, yet
it remains a common cause of death and disability. Current treatments are indiscriminate, reactionary and morbid
- none improve outcome. Guideline-based protocols use a templated approach to this immensely complex
process without addressing individual differences in contributory pathways or edema endophenotypes. The long
-term goal is to harness relevant individual data (genetic, molecular, imaging, physiologic) to direct a precision
medicine approach to treat TBI edema and related contusion expansion. This R01 focuses on logical next steps
to address existing knowledge gaps in a unique, key edema pathway involving Sulfonylurea receptor-1 (Sur1)
and its regulated cation channel Trpm4. Promising results from Sur-1 inhibition (Glyburide, GLY) in preclinical
and early clinical brain injury trials have generated exciting momentum in this pathway. The objective of this
translational R01 is to define the impact of Sur1-Trpm4 related genetic and protein variability on different edema
endophenotypes, contusion growth and response to inhibition in preclinical and human TBI. The rationale is that
identifying these individual differences directly informs patient risk-stratification, prognosis, trial design, and
targeted therapy; ultimately improving outcome. The central hypothesis is that Sur1 protein expression and
genetic variability influence the endophenotype, extent, and therapeutic response of TBI edema. Aim 1 defines
correlations between Sur1-Trpm4 expression and MRI edema endophenotypes in three clinically relevant
complementary mouse models. Aim 2 tests effects of Sur1 inhibition (GLY, inducible knockout) in these models
on MRI edema endophenotypes, contusion, and outcome. Aim 3 identifies impact of genetic variation in the Sur1
pathway on TBI edema and contusion growth (on imaging) in a single-center human test-cohort, and a
multicenter validation-cohort. The work is feasible as shown by robust preliminary results and the tools, expertise
and track record of successful collaborations among coinvestigators. This work is innovative in concept and
methodology: it shifts a guideline-based paradigm toward precision medicine, links clinically measurable edema
endophenotypes (MRI) with a molecular pathway and targeted inhibition in different TBI models, and uses a
novel transgenic mouse to generate Sur1-Trpm4 expression maps. This research is significant, with high impact
if successful: linking Sur1-Trpm4 expression and inhibition to MRI endophenotypes (Aims 1-2) directly translate
to identifying appropriate patients for targeted therapy and trials. Distinguishing high vs low risk genetic profiles
(Aim-3) will identify patients in whom Sur1-Trpm4 is a major contributor to TBI edema and contusion growth, and
channel inhibition may be highly beneficial- directing clinical care and trials. Ultimately, such knowledge has the
potential to transform precision-medicine care of this devastating secondary injury and improve TBI outcome.
