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Dissertation
Investigating Pathophysiology and Developing Therapies for EAE, a Mouse Model of MS: The Role of Sex Differences and TNFR2
Doctor of Philosophy (Ph.D.), Drexel University
Nov 2019
DOI:
https://doi.org/10.17918/es25-1874
Abstract
Epidemiological sex differences in autoimmune disease and chronic neuropathic pain (CNP) in humans has been well established as afflicting females predominately. However, despite the clear prevalence of autoimmunity and CNP being greater in females, animal research does not effectively address this sex difference. Using a novel mouse model for multiple sclerosis (MS), non-pertussis toxin experimental autoimmune encephalomyelitis (nPTX EAE), we explored sex differences in behavioral, pathophysiological, and biochemical changes following disease progression using female and male mice. We establish that, similar to MS patients, nPTX EAE induction causes CNP to develop in both sexes preceding motor symptoms and females develop motor symptoms earlier with greater severity over time compared to males. Our studies also establish a sexually dimorphic shift in the central nervous system (CNS) that ultimately leads to increased excitatory signaling indicative of synaptopathy in both spinal and supraspinal regions, despite EAE research predominately focusing on changes taking place in the spinal cord. A key mediator that previous research has demonstrated plays a role in exacerbation of inflammation and is known to increase glutamate-mediated transmission is tumor necrosis factor (TNF). Specifically, detrimental effects of TNF signaling that promote neurodegeneration and cell death under pathological conditions are associated with soluble TNF (solTNF) signaling through TNF receptor 1 (TNFR1). Conversely, previous studies have shown that transmembrane TNF (tmTNF) signaling through TNF receptor 2 (TNFR2) promotes tissue regeneration, beneficial immune cell modulation, and remyelination in autoimmunity and CNP. By selectively activating TNFR2 through the use of an agonist, p53-sc-mTNFR2, we establish that this therapeutic alleviates CNP in both sexes and alleviates female motor symptoms in nPTX EAE. The biochemical changes taking place following TNFR2 agonist administration are predominately seen supraspinally modulating myelin and immune cell associated proteins.
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Details
- Title
- Investigating Pathophysiology and Developing Therapies for EAE, a Mouse Model of MS
- Creators
- Kayla Lee Murphy - DU
- Contributors
- Daniel Marenda (Advisor) - Drexel University (1970-)John Bethea (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 29 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 11390; 991014632927804721