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Dissertation
Role of NF-kB in sympathetic hyperreflexia after spinal cord injury
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2023
DOI:
https://doi.org/10.17918/00001788
Abstract
Cardiovascular disease and immune dysfunction are two leading causes of morbidity and mortality in individuals with high-level spinal cord injuries (SCI). Sympathetic hyperreflexia is closely associated with peripheral immune dysfunction and cardiovascular disease. The neuroimmune system is known to modulate intraspinal plasticity within the spinal sympathetic reflex (SSR) circuit that leads to sympathetic hyperreflexia. Interestingly, there is persistent activation of NF-kB, a transcription factor complex that is activated by multiple cytokines, well below the SCI. We hypothesize that activation of NF-kB after SCI contributes to driving SSR circuit plasticity that results in the development of sympathetic hyperreflexia and associated autonomic dysreflexia. We further hypothesize that NF-kB signaling in microglia modulates their activation and polarization that contributes to heightened inflammation within the SSR circuit after SCI. To test this, we continuously and intrathecally delivered the NF-kB inhibitor DMAPT or vehicle immediately after a complete transection at thoracic spinal segment 3 in adult rats. Hemodynamic activity was recorded weekly to assess AD development for 12 weeks. Histological analyses of intraspinal plasticity in these animals further examines the role of NF-kB in driving sympathetic dysfunction and expression of microglia following SCI. We also assessed whether inhibition of NF-kB signaling in microglia modulates the quantity and polarization state of these CNS-resident immune cells at one-week and four-weeks post-SCI and whether this affects peripheral immune activity after SCI. We conditionally deleted the NF-kB activator Ikkb in Tmem119+ microglia in mice one week prior to a complete SCI. One or four weeks later, thoracolumbar spinal cords were isolated and processed for flow cytometry and/or RT-qPCR to assess how deletion of Ikkb in microglia affects microglial polarization and inflammatory activity after injury. The findings presented will demonstrate the critical role of NF-kB signaling in driving sympathetic hyperreflexia and associated development of autonomic dysreflexia as well as microglial signaling and inflammation after high-level SCI. Moreover, this research highlights novel cellular and pharmacological approaches to attenuate sympathetic dysregulation after SCI.
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Details
- Title
- Role of NF-kB in sympathetic hyperreflexia after spinal cord injury
- Creators
- Micaela Lucy O'Reilly
- Contributors
- Veronica J. Tom (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 213 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991021212314004721