Traumatic brain injury (TBI) is a growing health concern worldwide that affects a broad range of the population. As TBI is the leading cause of disability and mortality in children, several pre-clinical models have been developed using rodents at a variety of different ages; however, key brain maturation events are overlooked that leave some age groups more or less vulnerable to injury. Thus, there has been a large emphasis on producing relevant animal models to elucidate molecular pathways that could be of therapeutic potential to help limit neuronal injury and improve behavioral outcome. TBI involves a host of different biochemical events, including disruption of the cerebral vasculature and breakdown of the blood brain barrier (BBB) that exacerbate secondary injuries. A better of understanding of the mechanism(s) underlying cerebral vascular regulation will aid in establishing more effective treatment strategies aimed at improving cerebral blood flow restoration and preventing further neuronal loss. Our studies reveal an age-at- injury dependence on the Angiopoetin-Tie2 axis, which mediates neuroprotection in a model of juvenile TBI following cortical controlled impact (CCI) that is not seen in adult mice. The protection observed was mediated, in part, by the microvascular response to CCI injury and prompted further detailed analysis of the larger arteriole network across several mouse strains and models of TBI. Our second study revealed both a model and species dependent effect on a specialized network of arteriole vessels, called collaterals after trauma. We demonstrated that a repetitive mild TBI (rmTBI) can induce collateral remodeling in C57BL/6 but not CD1 mice; however, CCI injury had no effect on collateral changes in either strain. Together, these findings demonstrate an age-dependent and species/model dependent effect on vascular remodeling that highlights the importance of individualized therapeutics to TBI. / Ph. D. / Traumatic brain injury (TBI) is the most frequent cause of death in adults and children in the developed world and children are at the greatest risk of injury. In the United States alone there is a reported incidence of 1.7 million injuries a year and about half of these injuries are to children. Patients that survive TBI experience long-term neurological disabilities as there is not an effective treatment available. While the initial brain trauma cannot be treated, preventing further damage of delayed secondary responses of injury has garnered attention from researchers to better understand how the injury progresses. In order to mimic TBI in the lab, scientist use animal models of TBI to better understand the mechanism(s) involved in injury with the purpose of creating pharmacological targets to mitigate the effects of further tissue damage. While there are many cell types within the brain that are affected after TBI, our studies focus on endothelial cells that line the vascular system and allow for the circulatory function of blood to supply energy to the neurons of the brain. Our mouse model mimics the effects of sustaining a focal brain injury and we are interested in how the juvenile brain responds to this injury. We have found that juvenile mice are better protected after brain injury as they have less tissue damage compared to adult mice and we attribute this protection to better blood vessel numbers and function. While we observed changes to the vascular network in the juvenile model, this prompted studies to focus on other models of TBI to understand how blood vessels respond to a concussive-like injury. In these studies, we found that a particular species of mouse and the less severe injury prompted a special type of blood vessels to increase their diameter that was not seen in the more severe model of TBI. Taken together our findings demonstrate an age-dependent and species/model dependent effect on blood vessel remodeling.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/85566 |
| Date | 04 May 2017 |
| Creators | Brickler, Thomas Read |
| Contributors | Veterinary Medicine, Theus, Michelle H., Rossmeisl, John H. Jr., Matson, John B., Eyestone, Willard H. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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