Browsing by Author "Palmer, Alexandra L."

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    Elucidating the role of cystatin c in astrocytes in multiple sclerosis
    (2020-08-20) Palmer, Alexandra L.; Ousman, Shalina S.; Yong, Voon Wee; Antel, Jack P.; Kurrasch, Deborah M.; Kuipers, Hedwich F.; Jirik, Frank Robert
    Multiple sclerosis (MS) is one of the most common neurological disabilities of young adults. During the disease course there are a variety of molecules that become dysregulated, one of them being cystatin C (CysC). CysC is a small molecule inhibitor of cysteine cathepsins and is implicated in a variety of biological processes. The role of CysC in MS remains undetermined. Astrocyte reactivity is well noted in the MS literature and contributes to pathological processes during disease development and progression. This thesis set out to 1) characterize the expression of CysC in MS and the animal model, experimental autoimmune encephalomyelitis (EAE), 2) clarify the role of CysC in astrocytes and, 3) determine whether CysC can be therapeutically targeted. CysC expression was characterized in both MS and EAE central nervous system (CNS) samples. The expression of CysC was found to be increased in both MS and EAE brain and spinal cord samples, its expression overlapped with astrocytes, and a loss of CysC (CysCKO) in EAE ameliorated disease. This attenuation of clinical disability in CysCKO EAE mice was associated with a CNS intrinsic effect. A mixed glial culture system was then used to explore the effect of CysC on the response of astrocytes to pro-inflammatory stimuli. From this, it was found that CysCKO glia reduced cytokine and chemokine production in response to lipopolysaccharide (LPS) and increased cytokine and chemokine production upon activation by Interleukin-1beta + interferon-gamma, however CysC may not mediate this effect through the astrocyte signalling pathways STAT1, STAT3, or NF-kappaB. Lastly, Valsartan, a generic medication with the ability to reduce serum CysC levels in humans, was examined to see if it could therapeutically decrease CysC levels in vivo during EAE. Valsartan decreased CysC levels and delayed disease onset, however its effect did not appear to be mediated through astrocytes. Finally, an astrocyte-specific CysC conditional KO mouse was developed to more directly interrogate the role of CysC in astrocytes in vivo during EAE. This thesis provides novel evidence that CysC may influence astrocyte cytokine and chemokine secretion and may be a potential therapeutic target in MS.