Degree Type

Dissertation

Date of Award

2018

Degree Name

Doctor of Philosophy

Department

Kinesiology

Major

Neuroscience

First Advisor

Marian L. Kohut

Abstract

Neuroinflammation has emerged as a pathological component of neurodegenerative disease onset and progression, including Parkinson’s disease. Given the current absence of disease-modifying therapies for this progressive disorder, approaches have now begun to explore the inflammatory burden that detrimental host factors place on the brain and how they can drive disease development. Our lab has identified the novel expression of the double-stranded RNA-dependent protein kinase (PKR) within the rodent brain following i) metabolic inflammation (diet-induced obesity), ii) viral infection (non-neurotropic influenza), and iii) bacterial sepsis (lipopolysaccharide). PKR stereotypically functions as an antiviral kinase, but has been implicated as a signal transduction element in response to a number of cell stresses. This biological target has been proposed to be upstream of inflammatory signaling cascades that contribute to, and aggravate, Parkinsonian pathology. By studying CNS PKR expression in three host conditions known to perturb CNS homeostasis through pro-inflammatory insult of the brain, our lab has characterized the cellular and molecular level expression of PKR in animal models and attempted to determine this signal’s possible role in Parkinson’s disease pathogenesis. Our results suggest that PKR serves as a cell stress signal that may precede neurodegeneration and functions to promote apoptosis and inflammation. Studying PKR’s expression across a broad variety of host states may lead to the development of meaningful anti-inflammatory therapeutics that may be used against Parkinson’s disease and related conditions.

Copyright Owner

Matthew Aric Jefferson

Language

en

File Format

application/pdf

File Size

211 pages

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