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Dissertation
Mitigating secondary conditions of injury and disease: the dichotomy of soluble and transmembrane tumor necrosis factor
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2024
DOI:
https://doi.org/10.17918/00010439
Abstract
Spinal cord injury (SCI) is a devastating condition which negatively impacts an individual's immune system. The spleen is a major immune organ, and its innervation is disrupted after mid-thoracic SCI. Pre-synaptic neurons from supraspinal areas of the CNS synapse on interneurons in the thoracic spinal cord before exciting the sympathetic chain to the spleen. Unlike sympathetic preganglionic neurons, interneuron activation is increased after high-thoracic SCI and interestingly, blocking chronic inflammation in CNS after injury is effective in decreasing interneuron activity and improve immune function. However, how interneuron activation after mid-thoracic (T9) SCI impacts the immune function remains largely unknown. Furthermore, non-resolved chronic inflammation after injury may contribute to the development in SCI induced immune dysfunction as chronic inflammation has various roles in promoting disease and tissue damage. After SCI, sTNF is the first pro-inflammatory cytokine at the site of injury and remains elevated for >3 weeks following injury. Our lab has previously reported that inhibiting sTNF in the cord after injury improves antiviral immunity and decreases hyperexcitability of interneurons in the innervation of the sympathetic nervous system. The work in this thesis aims to understand how sTNF impacts immune function after T9-SCI and the involvement of sTNF/TNFR1 activation on spinal cord interneurons. In addition to immune dysfunction, there are a myriad of other secondary conditions. Previous work in our lab investigated how promoting TNFR2 after peripheral nerve injury and EAE, a mouse model of MS, mitigated the chronification of pain. Unlike TNFR1, TNFR2 activation is neuroprotective and reduces inflammation. After SCI, chronic neuroinflammation may negatively impact pain processing centers of the brain leading to pathophysiological changes which contribute to chronic pain. The work in this thesis covers preliminary reports of investigating the effects of a novel TNFR2 therapy in preventing the chronification of pain after T9-SCI. For both conditions there are currently no therapies and chronic neuropathic pain affects more than 70% of individuals with injury. Mitigating the effects of immune dysfunction and chronic pain will improve the quality of life for individuals with SCI and decrease mortality.
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Details
- Title
- Mitigating secondary conditions of injury and disease
- Creators
- Tetyana Martynyuk
- Contributors
- Ryan J. Petrie (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 102 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 991021889314604721