Operation Brain Trauma Therapy (OBTT) is a multicenter pre-clinical drug screening consortium testing promising therapies for traumatic brain injury (TBI) in three well-established models of TBI in rats--namely, parasagittal fluid percussion injury (FPI), controlled cortical impact (CCI), and penetrating ballistic-like brain injury (PBBI). This article presents unique characterization of these models using histological and behavioral outcomes and novel candidate biomarkers from the first three treatment trials of OBTT. Adult rats underwent CCI, FPI, or PBBI and were treated with vehicle (VEH). Shams underwent all manipulations except trauma. The glial marker glial fibrillary acidic protein (GFAP) and the neuronal marker ubiquitin C-terminal hydrolase (UCH-L1) were measured by enzyme-linked immunosorbent assay in blood at 4 and 24 h, and their delta 24-4 h was calculated for each marker. Comparing sham groups across experiments, no differences were found in the same model. Similarly, comparing TBI + VEH groups across experiments, no differences were found in the same model. GFAP was acutely increased in injured rats in each model, with significant differences in levels and temporal patterns mirrored by significant differences in delta 24-4 h GFAP levels and neuropathological and behavioral outcomes. Circulating GFAP levels at 4 and 24 h were powerful predictors of 21 day contusion volume and tissue loss. UCH-L1 showed similar tendencies, albeit with less robust differences between sham and injury groups. Significant differences were also found comparing shams across the models. Our findings (1) demonstrate that TBI models display specific biomarker profiles, functional deficits, and pathological consequence; (2) support the concept that there are different cellular, molecular, and pathophysiological responses to TBI in each model; and (3) advance our understanding of TBI, providing opportunities for a successful translation and holding promise for theranostic applications. Based on our findings, additional studies in pre-clinical models should pursue assessment of GFAP as a surrogate histological and/or theranostic end-point.

Operation Brain Trauma Therapy (OBTT) is a fully operational, rigorous, and productive multicenter, pre-clinical drug and circulating biomarker screening consortium for the field of traumatic brain injury (TBI). In this article, we synthesize the findings from the first five therapies tested by OBTT and discuss both the current work that is ongoing and potential future directions. Based on the results generated from the first five therapies tested within the exacting approach used by OBTT, four (nicotinamide, erythropoietin, cyclosporine A, and simvastatin) performed below or well below what was expected based on the published literature. OBTT has identified, however, the early post-TBI administration of levetiracetam as a promising agent and has advanced it to a gyrencephalic large animal model--fluid percussion injury in micropigs. The sixth and seventh therapies have just completed testing (glibenclamide and Kollidon VA 64), and an eighth drug (AER 271) is in testing. Incorporation of circulating brain injury biomarker assessments into these pre-clinical studies suggests considerable potential for diagnostic and theranostic utility of glial fibrillary acidic protein in pre-clinical studies. Given the failures in clinical translation of therapies in TBI, rigorous multicenter, pre-clinical approaches to therapeutic screening such as OBTT may be important for the ultimate translation of therapies to the human condition.

Current approaches have failed to yield success in the translation of neuroprotective therapies from the pre-clinical to the clinical arena for traumatic brain injury (TBI). Numerous explanations have been put forth in both the pre-clinical and clinical arenas. Operation Brain Trauma Therapy (OBTT), a pre-clinical therapy and biomarker screening consortium has, to date, evaluated 10 therapies and assessed three serum biomarkers in nearly 1,500 animals across three rat models and a micro pig model of TBI. OBTT provides a unique platform to exploit heterogeneity of TBI and execute the research needed to identify effective injury specific therapies toward precision medicine. It also represents one of the first multi-center pre-clinical consortia for TBI, and through its work has yielded insight into the challenges and opportunities of this approach. In this review, important concepts related to consortium infrastructure, modeling, therapy selection, dosing and target engagement, outcomes, analytical approaches, reproducibility, and standardization will be discussed, with a focus on strategies to embellish and improve the chances for future success. We also address issues spanning the continuum of care. Linking the findings of optimized pre-clinical consortia to novel clinical trial designs has great potential to help address the barriers in translation and produce successes in both therapy and biomarker development across the field of TBI and beyond.

Tuberous sclerosis (TSC) is a multi-system disorder characterized by hamartomatous tumors and abnormal brain development, with multiple foci of disrupted neuronal migration and giant dysmorphic neurons within cortical tubers. TSC is associated with mutations in 2 genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively. The functions of these proteins have yet to be determined. Recently, the Drosophila homologue of TSC2, gigas, has been shown to be required for the G2/M transition of the cell cycle. However, the mechanism of this action remains unknown. Because the cyclin-dependent kinase CDK1 forms a complex with cyclin B1 to trigger the G2/M transition, we hypothesized that tuberin interacts with CDK1 to regulate its activity. In the study reported in this paper, we have used co-immunoprecipitation and confocal microscopy to demonstrate that tuberin interacts with and co-localizes with CDK1 and its binding partner cyclin B1 in multiple cell types. We also demonstrate that hamartin interacts with CDK1 and cyclin B1. We further present evidence that tuberin interacts with the other regulatory subunit of CDK1, cyclin A. These findings suggest a direct role for tuberin and hamartin in modulating the activity of CDK1 during G2 and the G2/M transition. This is the first description of a role for both tuberin and hamartin in a common cellular function, providing a potential mechanism for the identical clinicopathologic manifestations that result when either of these proteins are inactivated.

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