For decades, there has been a critical gap in translating preclinical work on mechanisms of contusion expansion
in traumatic brain injury (TBI) to clinical therapies that improve outcome. This is important because contusion
expansion is a major driver of unfavorable outcome in TBI with up to 5X increase in morbidity and mortality, yet
there are no treatments or biomarkers to identify patients at risk. There is immense potential to address this
issue because unlike primary injury, contusion expansion results from host response to the initial TBI and thus
is a modifiable secondary injury. Guideline-based care uses a reactive templated approach to this hugely
complex process without addressing individual differences in contributory pathways; it does not prevent or limit
contusion expansion and struggles to mitigate the life-threatening consequences. Such homogeneous strategies
for a heterogeneous disease have unsurprisingly led to many failed clinical trials. Our long-term goal is to
harness relevant individual data (molecular, single-cell [SC], genetic, imaging) to direct precision medicine for
TBI contusion expansion. This R21 addresses existing knowledge gaps in a promising therapy for contusion
expansion being primed for translation: Glyburide (GLY). Existing research generated exciting momentum but
also revealed major individual differences in GLY targets that could affect drug-response/successful translation.
Our objective is to use SC and proteomic strategies to molecularly endotype GLY-targeted pathways of
contusion expansion in human TBI. The rationale is that it allows us to better understand heterogeneous benefits
and opportunities of GLY and optimize translation: it informs cellular origins of key targetable and measurable
contusion expansion pathways. The central hypothesis is that a subset of quantifiable cell-type specific
differentially expressed genes, pathways and proteins targeted by GLY identify risk for TBI contusion expansion.
Aim 1 demonstrates that cerebrospinal fluid (CSF) SC transcriptomic signatures endotype GLY-targeted
contusion expansion in humans. Aim 2 demonstrates that contusion expansion is preceded by GLY-targetable
protein biomarkers changes. The aims are synergistic: cell-type differential gene expression (Aim 1) informs
likely sources of measurable CSF biomarkers (Aim 2) of contusion expansion. The work is feasible given exciting
pilot data, an existing TBI biobank, an established multidisciplinary team and bioinformatic pipelines. It is
innovative as it shifts a guideline-based approach to precision medicine, creates a first-in-human atlas of CSF
SC response in TBI, and identifies contusion expansion biomarkers in pathways targeted by a drug being tested
in human TBI. The expected impact includes molecular endotype-based risk-stratification and enriched patient-
selection for GLY trials (high risk, pharmacodynamic response). Unique cellular components that drive contusion
expansion combined with early clinically measurable CSF biomarkers can guide unprecedented cell- and target-
precise therapy including novel (preventive) druggable targets. This lays the foundation for a paradigm shifting
SC-based precision medicine approach to understand, monitor, and treat a devastating secondary injury in TBI.
