A Single Cell and Proteomic Precision Medicine Approach to Glyburide Responsive Contusion Expansion in Severe Traumatic Brain Injury

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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.