Electronic Poster | Session 2

014 – Elucidating the role of cystatin C in astrocytes in multiple sclerosis

Alexandra Palmer (1) – Vahid Hoghooghi (1) – Hedwich Kuipers (2) – Paul Kubes (3) – V. Wee Yong (4) – Shalina Ousman (2)
Hotchkiss Brain Institute, Neuroscience/The University of Calgary, Calgary, Canada (1) – Hotchkiss Brain Institute, Clinical Neurosciences/The University of Calgary, Calgary, Canada (2) – Snyder Institute for Chronic Diseases, Physiology & Pharmacology/The University of Calgary, Calgary, Canada (3) – Hotchkiss Brain Institute, Clinical Neurosciences & Oncology/The University of Calgary, Calgary, Canada (4)

Multiple sclerosis (MS) is a disease of unknown etiology that is characterized by inflammation, glial cell activation, demyelination, and axonal loss of the central nervous system (CNS). Multiple cell types are involved in the pathogenesis of MS, including astrocytes. Astrocytes were once considered passive responders in MS; however recent literature indicates that astrocytes play a more active role than previous appreciated. This is due to their ability to become dysfunctional and contribute to disease progression and pathology during CNS disease and injury. Thus, the goal of our lab is to identify factors that are involved in the disease-promoting functions of astrocytes in MS. The expression of a variety of proteins become dysregulated during MS. One of these proteins is Cystatin C (CysC) and conflicting evidence exists as to whether it is protective or detrimental in MS. CysC has been found to be increased in the brains of MS patients, which we have confirmed in a small cohort of secondary progressive MS patients, as well as in the CNS of mice with experimental allergic encephalomyelitis (EAE), a model of MS. Upon additional examination we found that CysC was localized to astrocytes in both MS patients and EAE animals, and that induction of EAE in globally knocked out CysC mice resulted in a decrease in disease severity. We further explored the relationship between CysC and astrocytes and found that in the absence of CysC, astrocytes secrete less pro-inflammatory cytokines and chemokines. Based on these findings we hypothesize that CysC plays a detrimental role in EAE by promoting a pro-inflammatory environment via astrocyte activation. To supplement this hypothesis, I will investigate how CysC expression in astrocytes influences the migration and activation of infiltrating peripheral immune cells. I will also establish if CysC expression specifically in astrocytes modulates EAE by utilizing a CysC conditional knockout mouse. Furthermore, we will test if Valsartan, a hypertension drug that reduces CysC levels, will suppress the pro-inflammatory nature of disease-associated astrocytes and EAE clinical disability. Altogether, this project will establish if CysC promotes astrocyte dysfunction in MS, and whether it is a potential therapeutic target to combat disease progression.