Date of Completion

2-4-2019

Embargo Period

2-4-2019

Keywords

multiple sclerosis, extracellular vesicle, astrocyte, T cell, inflammation

Major Advisor

Dr. Stephen Crocker

Associate Advisor

Dr. Kyle Baumbauer

Associate Advisor

Dr. Robert Clark

Associate Advisor

Dr. Royce Mohan

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Extracellular vesicles play important and crucial roles in orchestrating and modulating cellular responses under both normal and diseased conditions. In my thesis work, I studied extracellular vesicle release from astrocytes during CNS inflammation. Moreover, I studied how extracellular vesicles can modulate and drive the immune response during active CNS disease. Extracellular vesicles encompass a heterogeneous group of cell-derived vesicles that have been found to be important in initiating and directing pathological responses.

In my thesis work, I focused on the characterization and quantification of extracellular vesicles from astrocytes under normal and inflammatory conditions. As described in chapter three of my thesis, I developed a semi-quantitative flow cytometry method for analysis of extracellular vesicles from astrocytes and found that following cytokine challenge in vitro, astrocytes releases more extracellular vesicles. Additionally, I studied whether astrocyte-derived extracellular vesicles could be detected in peripheral circulation and if their numbers increased in a mouse-model of multiple sclerosis. Allowing for the potential of astrocyte-derived extracellular vesicles to be potent biomarkers to monitor disease progression.

Furthermore, I studied whether extracellular vesicles could modulate the immune system during active disease. As described in chapter four, I found that injection of plasma extracellular vesicles into animals during the height of clinical disease in a mouse model of multiple sclerosis induced a relapsing-remitting phenotype that seemed to be driven by an unidentified interaction between the blood coagulation factor fibrinogen and CD8+ T cells. Additionally, post-translational modifications analysis of the proteomic content of plasma extracellular vesicles identified extensive citrullination occurs on proteins in blood plasma that may be causative in driving the immune responses observed.

In general, my thesis studies focused on the characterization and effect of extracellular vesicles from a CNS-cell source and in an animal model of multiple sclerosis.

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