Date of Award

Spring 2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor

Riyi Shi

Committee Chair

Riyi Shi

Committee Member 1

Kevin Hannon

Committee Member 2

Eric Nauman

Committee Member 3

Kevin Otto

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating neuropathy that affects nearly 2.5 million people worldwide. Despite substantial efforts, few treatments are currently available largely due to limited knowledge of pathogenic mechanisms underlying the disease. The immune-inflammatory nature of the pathology has prompted investigation of the role of oxidative stress in disease development and progression; however targeting reactive oxygen species for neutralization has had marginal success therapeutically, suggesting that an alternate oxidative stress-related target would prove beneficial. Recently, our lab has implicated acrolein, a highly reactive aldehyde that is both a byproduct and catalyst of lipid peroxidation, as a potential therapeutic target and biomarker for MS diagnosis and symptom monitoring. We have shown that acrolein is elevated in clinical MS cases and experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Furthermore, pharmacological sequestering of acrolein afforded a neuroprotective effect by suppressing tissue acrolein level, slowing disease progression, and decreasing symptom severity. Acrolein can also be produced exogenously as a pollutant from combustion engine exhaust, industrial processing, burning of tobacco and overheated cooking oil vapors. The pathogenic role of endogenous acrolein in MS raises the possibility that environmental exposure to acrolein could potentially increase MS risk or exacerbate MS symptoms. Using a respiratory exposure model in combination with urinary detection of an acrolein metabolite and immunoblotting assessment of tissue acrolein-lysine adducts, we have ascertained that inhalation of acrolein can cause accumulation of acrolein in mice systemically and locally within the CNS. Additionally clinical acrolein assessment using urine and serum samples revealed that MS patients who self-reported as smokers demonstrated higher systemic acrolein levels and demonstrated greater motor deficit compared to MS patients that did not smoke. These observations indicate that acrolein is likely contributing to the mechanisms underlying symptom development in EAE and MS and may serve as a therapeutic target and biomarker for diagnosis, guiding treatment regimens and monitoring relapses.