There is a fundamental gap in translating preclinical work on complex underlying mechanisms of cerebral edema in traumatic brain injury (TBI) to critically needed biomarkers and targeted/preventive therapies for improving outcomes in humans. This is an important problem because indiscriminate clinical approaches to cerebral edema remain reactionary and morbid - compounding a problem that is a fundamental contributor to death and disability in TBI. The long-term research goal is to better understand the roles and interactions of edema pathways in human TBI. This will focus innovation of successful targeted treatments. The overall objective of this K23 is to develop a comprehensive approach towards understanding a unique, key pathway of cerebral edema in human TBI involving a transmembrane protein: Sulfonylurea Receptor-1 (Sur1). Founded on the central dogma of biology, this proposal evaluates the Sur1-cerebral edema relationship in TBI from multiple angles by investigating Sur1 expression and genetic variability in humans, and complementing this with a clinically relevant, unique, edema-generating mouse-model. The central hypotheses are that 1) Sur1 levels and genetic variability influence cerebral edema and 2) Sur1 expression patterns guide treatment efficacy. The hypotheses have been formulated upon preliminary data generated by the applicant that strongly suggest feasibility. The rationale for the proposal is that complementing Sur1 expression and genetics in human TBI with a relevant animal model, has the potential to directly translate to improving clinical care and outcomes. This is expected to inform patient risk stratification, monitoring, prognosis, and targeting/developing specific therapies.
Aim 1 evaluates the relationship between human Sur1 expression (detected in cerebrospinal fluid, CSF, by enzyme linked immunosorbent assay, ELISA), cerebral edema, and TBI outcomes.
Aim 2 evaluates the human Sur1 gene (ABCC8) tag-single nucleotide polymorphism (SNP) associations with cerebral edema in TBI.
Aim 3 generates a temporo-spatial map of Sur1 expression (by validated techniques) and quantifies effects of Sur1 inhibition by glyburide in an edema-generating mouse-model of TBI. The approach is innovative, in the applicant's opinion, because it molecularly complements generic intracranial pressure (ICP) monitoring and responses to cerebral edema by focusing on a key pathway, and uses a multifaceted approach to bridge the gap between animal models and human disease.
These aims are expected to establish the utility of Sur1 as a novel biomarker and evaluate it as a preventive therapeutic target against edema. The proposed work is significant because it has potential groundbreaking implications for monitoring and preventing cerebral edema that may reduce morbidity and mortality, not just in TBI, but in many other neurological disorders. The research plan is augmented by expert mentoring and rigorous didactic training. Together, this will provide the candidate with essential career development in translational research methodologies and the science of biomarkers, modern genetics, and statistics. These synergistic tools cultivate skills necessary for transition to independence. It sets the stage for R01-projects evaluating the interplay between Sur1 expression, genetics and inhibition in clinical trials. This work will uniquely position the investigator as a future leader in the development of individualized targets against cerebral edema to improve outcomes in TBI.
This research is important to public health because cerebral edema remains a central cause of death and disability in TBI and many acute neurological conditions, affecting millions of people. Research advances have unveiled nuanced pathophysiologic pathways involved in cerebral edema in animal models, however translation and exploration in humans has been limited resulting in available treatments remaining reactionary, non-specific, and inadequate. By advancing insight into a key pathway involved in cerebral edema in human TBI, and evaluating a targeted therapy in a unique and relevant preclinical model, this work directly informs the NIH mission of developing fundamental knowledge that helps reduce human disability.
| Jha, Ruchira Menka; Koleck, Theresa A; Puccio, Ava M et al. (2018) Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury. J Neurol Neurosurg Psychiatry 89:1152-1162 |
| Jha, Ruchira M; Elmer, Jonathan; Zusman, Benjamin E et al. (2018) Intracranial Pressure Trajectories: A Novel Approach to Informing Severe Traumatic Brain Injury Phenotypes. Crit Care Med 46:1792-1802 |
| Jha, Ruchira M; Molyneaux, Bradley J; Jackson, Travis C et al. (2018) Glibenclamide Produces Region-Dependent Effects on Cerebral Edema in a Combined Injury Model of Traumatic Brain Injury and Hemorrhagic Shock in Mice. J Neurotrauma 35:2125-2135 |
| Adams, Solomon M; Conley, Yvette P; Wagner, Amy K et al. (2017) The pharmacogenomics of severe traumatic brain injury. Pharmacogenomics 18:1413-1425 |
| Jha, Ruchira M; Kochanek, Patrick M (2017) Adding insight to injury: a new era in neurotrauma. Lancet Neurol 16:578-580 |
