Investigating the role of subcellular localisation of aquaporin 4 in astrocytes after traumatic spinal cord injury

Halsey, Andrea Melissa (2021). Investigating the role of subcellular localisation of aquaporin 4 in astrocytes after traumatic spinal cord injury. University of Birmingham. Ph.D.

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Traumatic spinal cord injury (SCI) is a debilitating condition that affects millions of people worldwide. Many people who receive a SCI suffer from paralysis and a reduced quality of life. Most of the complications of SCI occur secondary to the initial injury over a period of days to years. Currently, there are no pharmacological interventions to prevent secondary features of SCI, such as edema and scarring, meaning symptom management is the only available treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and facilitates water flux across the blood-spinal-cord-barrier (BSCB). Previous work has demonstrated that AQP4 can be regulated by subcellular relocalization to the cell membrane, which alters its permeability, in a mechanism requiring calmodulin (CaM) and protein kinase A (PKA). AQP4 has been frequently associated with a number of secondary pathologies after SCI, including the formation of cytotoxic edema, and the migration of astrocytes preceding the formation of the glial scar border, both requiring a site-specific localization of AQP4. In this study, we aimed to investigate whether treatment with the inhibitors of subcellular AQP4 relocalization investigated in vitro could limit the formation of these secondary pathologies in vivo, using a rat dorsal column crush spinal cord injury model. This study illustrates that treatment with inhibitors of CaM, with the licenced drug trifluoperazine (TFP), or PKA, in a rat dorsal column crush SCI model, inhibited AQP4 localization to the blood-spinal-cord barrier, ablated SCI edema, lessened functional deficit, and reduced the size and density of the glial scar formed compared with untreated animals. In conclusion, this study demonstrates that targeting the mechanism of CaM/PKA-mediated cell-surface localization of AQP4 is a plausible approach for the treatment of traumatic SCI.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Inflammation and Ageing
Funders: None/not applicable
Subjects: Q Science > QP Physiology


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