Translational Studies of Acute and Chronic Traumatic Brain Injury: Molecular Profiling of Tissue and Biofluids
Weisz, Harris Alexander
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Traumatic brain injury (TBI) is a leading contributor to the global burden of disease. Despite the growing awareness of TBI and years of research into biomechanics and pathophysiologic mechanisms, there is still a lack of effective therapies to treat patients. To better understand the genomic landscape in both acute and chronic TBI, microarrays and next generation sequencing (NGS) were performed to gain insight into potential molecular mechanism of injury. Translational studies were initially performed in rats using a well-established model of TBI, fluid percussion injury (FPI). Rats were sacrificed, and tissue harvested at various post-injury intervals (4 TBI, 4 Sham control at 24hr, 2 wk, 1, 2, 3, 6, and 12-month post-TBI, n= 56). Using a bioinformatic platform (Ingenuity Pathway Analysis), these studies identified genes and prominent cell signaling pathways that are dysregulated weeks to months after TBI. Genes and pathways were predominately associated with immune and regenerative signaling. Later, sequencing revealed TBI-induced changes in small non-coding RNAs, known as microRNAs (miRNAs) in the rat hippocampus up to 12 months post-injury. Predicted gene targets of the differentially expressed rat miRNAs have been shown to be involved in inflammatory cell signaling pathways. Prinicipal component analysis (PCA) showed that gene and miRNA profiles could be used to identify TBI rats at all acute and chronic intervals. Pilot studies in two different rat TBI models (FPI and controlled cortical impact) showed that it was possible to measure distinct changes in peripheral (serum) miRNA profiles representative of each injury model, respectively. To gain greater insight into the mechanistic underpinnings of human TBI, miRNA-seq was performed on human TBI serum samples from both acutely injured and chronically injured patients (12 age-matched control and 39 archived TBI samples representing 24, 48, 96 hr post-ED admission and 2 to 32 years post-injury). Notably, human TBIs can be identified by serum miRNA profiles across all acute and chronic time points and at 24 hr, miRNA profiles discriminate between focal and diffuse injuries. The predicted gene targets of these discriminating miRNAs are involved in nervous system related signaling and immune function, highlighting their potential utility as ‘molecular fingerprints’ for TBI diagnosis.