Date of Award

12-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Basic Medical Sciences

Committee Chair

Riyi Shi

Committee Member 1

Brad Duerstock

Committee Member 2

Kevin Hannon

Committee Member 3

Eric Nauman

Committee Member 4

James Walker

Abstract

The prevalence of blast-induced traumatic brain injury (bTBI) is steadily increasing due to escalated terror activities and constitutes the signature injury associated with the current military conflicts. Specifically, a mild-bTBI is the most common injury encountered by our military personnel. This type of injury presents a problem because the individual is initially asymptomatic and functional. Increasing studies have suggested that this type of injury may produce long-term neurological consequences that affect the resilience and the performance of soldiers both on and off the battlefield. One such example is an increased susceptibility to Parkinson’s disease (PD) by as many as three folds post-blast injury when compared to the general population. A critical strategy aiming at curtailing this alarming trend is to further our knowledge of pathogenic mechanisms responsible for the escalation of post trauma neurodegenerative diseases. The specific aim of this investigation was to identify the molecular mechanisms underlying the susceptibility to PD in post-blast rats. To this end, we have identified acrolein, a highly reactive aldehyde that persists days to weeks following CNS injury and perpetuates oxidative insult, as a point of convergence between bTBI and PD. Specifically, we have found that the elevation of acrolein post-blast is capable of triggering pathological changes in the vicinity of the basal ganglion, a known location of brain damage in PD. In particular, we have found signs of neuroinflammation and protein aggregation in blast animals that resembles the pathology in PD, although to a lesser extent. In addition, although a mild blast injury alone cannot elicit typical motor deficits seen in a PD model, additional application of a subthreshold PD-inducing toxin could lead to such deficits. Taken together, we hypothesize that bTBI triggers neurochemical events, such as neuroinflammation and oxidative stress, galvanized by acrolein, could increase the susceptibility of the blast-injured rats to PD and when other PD-triggering factors are present. As such, we hypothesize that acrolein is a key pathological factor linking bTBI and the development of PD in our rat model.

The results from this project are expected to advance our understanding of the long-term consequences of blast-related injuries leading to the development of PD. These efforts could eventually lead to the establishment of biomarkers for an earlier diagnosis as well as strategies for prevention and treatment to curtail the elevating incidence of post-bTBI PD, and significantly improve the quality of life for our men and women who suffer a great deal to ensure our freedom.

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