Pro-oxidative and Pro-inflammatory Mechanisms of Brain Injury in Experimental Animal and 3D Cell Culture Model Systems
Cho, Hyung Joon
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The pro-oxidative and pro-inflammatory mechanisms have been implicated in various human diseases including neurological and psychiatric disorders. However, there is only limited information available on the etiology in the progression of neurological damage to brain. The emergence of tissue engineering with the growing interest in mechanistic studies of brain injury now raises great opportunities to study complex physiological and pathophysiological process in vitro. Therefore, the prime goals of this study include: (1) Determination of the molecular and cellular mechanisms responsible for blast- and radiation-induced brain injuries and (2) Development of a three-dimensional (3D) model system in order to mimic in vivo-like microenvironments to further broaden our knowledge in pro-oxidative and pro-inflammatory mechanisms and their cellular responses within 3D constructs. In the first study, we demonstrated that blast exposure induced specific molecular and cellular alterations in pro-oxidative and pro-inflammatory environments in the brain and neuronal loss with adverse behavioral outcome. The results provide evidence that pro-oxidative and pro-inflammatory environments in the brain could play a potential role in blast-induced neuronal loss and behavioral deficits. In the second study, we investigated that fractionated whole-brain irradiation induced specific molecular and cellular alterations in pro-oxidative and pro-inflammatory environments in the brain along with elevation of reactive oxygen species (ROS)-generating protein (NOX-2) and microglial activation. Additionally, the contribution of NOX-2 in fractionated whole-brain radiation-induced oxidative stress was observed by dramatic amelioration of ROS generation after pharmacological inhibition of NOX-2. These results support that NOX-2 may play a pivotal role in fractionated whole-brain radiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain. In the third study, we developed an in vitro 3D experimental model of brain inflammation by encapsulating microglia in collagen hydrogel with computational analysis of 3D constructs. The results indicated that our newly developed in vitro 3D model system provides a more physiologically relevant environment to mimic in vivo responses. In conclusion, these data may be beneficial in defining a cellular and molecular basis of pathophysiological mechanisms of brain injuries. Furthermore, it may provide new opportunities for preventive and therapeutic interventions for patients with brain injuries and associated neurological disorders.
- Doctoral Dissertations