Date of Award

Spring 1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Monika Fleshner

Second Advisor

Lisa Dilling

Third Advisor

Michael W. Graner

Fourth Advisor

Christopher A. Lowry

Fifth Advisor

Robert S. Mazzeo

Abstract

Acute activation of the stress response modulates an adaptive series of physiological changes to optimize an organism's survival. One component of the stress response involves an induction of the innate immune system through the release of Hsp72, an endogenous danger associated molecular pattern rapidly released into the blood following stressor exposure. The mechanism of Hsp72 release is unknown, but recent findings suggest Hsp72 is release via the non-classical exosome releasing pathway. This dissertation explores the emerging role of exosomes during stress-induced immunomodulation. Exosomes, biologically active nanoparticles released by most cells in the body, encompass a variety of proteins and microRNA (miRNA) that can be modified in response injury, infection, or disease. The goals in this dissertation as follows: (1) characterize Hsp72 in the plasma, peripheral tissues, brain, and cerebrospinal fluid following acute stressor exposure; (2) investigate potential targets for stress-sensitive markers associated with exosomes; (3) explore the potential pathways activated during the stress response responsible for modulating exosomes; and (4) examine how stress-modified exosomes impact bacterial inflammation. We provide evidence in this dissertation that exposure to an acute stressor modifies Hsp72 expression and the miRNA character of circulating plasma exosomes in the absence of a pathogenic challenge or disease. Further, we identify sympathetic nervous system (SNS) activation as an important signal for part of the stress-evoked changes in circulating exosomes. Importantly, these stress-modified plasma exosomes contribute to enhanced host response during a bacterial challenge. Future research is necessary to determine both the cellular sources and targets of stress-modified exosomes.

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