The proposed research will use a personalized precision medicine approach to establish a preclinical model of chronic repetitive mild traumatic brain injury (rmTBI). The first objective of the proposed research is the elucidation of the blood molecular signature for chronic rat rmTBI. The second objective is to test whether administration of the neuroprotective agent neuregulin-1 (NRG-1) improves behavioral performance in this model. This is highly relevant because a significant military and veteran population exists that experiences persistent symptoms chronically following mTBI/concussion. The Next Generation Sequencing (NGS) technique, RNA-Seq, can identify characteristic expression patterns of exons, or a molecular signature, in blood samples drawn from stroke and TBI patients that can distinguish the injured patients from controls. The proposed study will employ RNA-Seq analysis in the development of an experimental animal model that will allow for control of model parameters, reducing the sample size, compared to human studies, needed to conclusively identify blood molecular signatures. This represents a step towards the development of a diagnostic tool that could be used to objectively identify patients who suffered rmTBI, resulting more targeted treatment. A significant benefit of this preclinical model is that it will support testing of experimental therapies, giving valuable functional and blood molecular information in return. This proposal includes an initial therapeutic trial with NRG-1. NRG-1 has the additional ability to reduce brain inflammation which could address the issue of persistent inflammation that has been demonstrated in chronically injured brains. This could also contribute to the improvement of behavioral outcomes.
The proposed research that will result in the development of a preclinical model of repetitive mild traumatic brain injury (TBI) is highly relevant to the military and veteran populations because it is estimated that up 30% of soldiers returning from active war zones have suffered TBIs with over 82% of these being mild TBI or concussions. Additionally, repetitive mild TBI/concussion has been receiving increasing emphasis in view of its prevalence in contact sports and the growing diagnosis of chronic traumatic encephalopathy (CTE). CTE has also been detected in military and veteran personnel.
