dc.contributor.author	Bailey, Zachary S.	en
dc.contributor.committeechair	VandeVord, Pamela J.	en
dc.contributor.committeemember	Xie, Hehuang David	en
dc.contributor.committeemember	Leung, Lai Yee	en
dc.contributor.committeemember	Lee, Yong Woo	en
dc.contributor.committeemember	Hall, Adam R.	en
dc.contributor.department	Biomedical Engineering	en
dc.date.accessioned	2017-09-07T08:00:19Z	en
dc.date.available	2017-09-07T08:00:19Z	en
dc.date.issued	2017-09-06	en
dc.description.abstract	Blast-induced neurotrauma (BINT) is a prevalent brain injury within both military and civilian populations due to current engagement in overseas conflict and ongoing terrorist events worldwide. In the early 2000s, 78% of injuries were attributable to an explosive mechanism during overseas conflicts, which has led to increased incidences of BINT [1a]. Clinical manifestations of BINT include long-term psychological impairments, which are driven by the underlying cellular and molecular sequelae of the injury. Development of effective treatment strategies is limited by the lack of understanding on the cellular and molecular level [2a]. The overall hypothesis of this work is that epigenetic regulatory mechanisms contribute to the progression of the BINT pathology and neurological impairments. Epigenetic mechanisms, including DNA methylation and histone acetylation, are important processes by which cells coordinate neurological and cellular response to environmental stimuli. To date, the role of epigenetics in BINT remains largely unknown. To test this hypothesis, an established rodent model of BINT was employed [3a]. Analysis of DNA methylation, which is involved in memory processes, showed decreased levels one week following injury, which was accompanied by decreased expression of the enzyme responsible for facilitating the addition of methyl groups to DNA. The one week time point also showed dramatic decreases in histone acetylation which correlated to decline in memory. This change was observed in astrocytes and may provide a mechanistic understanding for a hallmark characteristic of the injury. Treatment with a specific enzyme inhibitor was able to mitigate some of the histone acetylation changes. This corresponded with reduced astrocyte activation and an altered behavioral phenotype, which was characterized by high response to novelty. The diagnostic efficacy of epigenetic changes following blast was elucidated by the accumulation of cell-free nucleic acids in cerebrospinal fluid one month after injury. Concentrations of these molecules shows promise in discriminating between injured and non-injured individuals. To date, the diagnostic and therapeutic efforts of BINT have been limited by the lack of a mechanistic understanding of the injury. This work provides novel diagnostic and therapeutic targets. The clinical potential impact on diagnosis and therapeutic intervention has been demonstrated.	en
dc.description.degree	Ph. D.	en
dc.format.medium	ETD	en
dc.identifier.other	vt_gsexam:12649	en
dc.identifier.uri	http://hdl.handle.net/10919/78813	en
dc.publisher	Virginia Tech	en
dc.rights	In Copyright	en
dc.rights.uri	http://rightsstatements.org/vocab/InC/1.0/	en
dc.subject	Blast-induced neurotrauma	en
dc.subject	epigenetics	en
dc.subject	DNA methylation	en
dc.subject	Histone acetylation	en
dc.title	Epigenetic Mechanisms in Blast-Induced Neurotrauma	en
dc.type	Dissertation	en
thesis.degree.discipline	Biomedical Engineering	en
thesis.degree.grantor	Virginia Polytechnic Institute and State University	en
thesis.degree.level	doctoral	en
thesis.degree.name	Ph. D.	en

Epigenetic Mechanisms in Blast-Induced Neurotrauma

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