Grant: Project Grant

Multiple sclerosis (MS) is a debilitating autoinflammatory demyelinating disease that commonly presents with a relapsing remitting course (RRMS) that can convert to a secondary progressive form (SPMS) or that less commonly presents as a primary progressive form (PPMS). Current treatments for MS are immunomodulatory and are mainly effective for treatment of RRMS patients. Therapeutic options for progressive MS (PMS) patients are limited and this is an area of unmet clinical need. Neuronal pathology and cell death underlie the neurological disability and cognitive dysfunction that is evident in PMS. Pathological inflammation within the central nervous system (CNS) results from multiple noxious signaling events that contribute to the neurodegenerative component and for this reason targeting the neuronal response to injury rather than individual noxious stimuli is a powerful strategy for the development of neuroprotective agents. We have discovered that immune system related genes including interferon response genes are upregulated in pathologically inflamed neurons in patients with Multiple Sclerosis and in the Experimental Autoimmune Encephalomyelitis animal model. Prediction of transcriptional regulators of these genes has identified the immune-related upstream regulators Stat1 and Irf5 to also be significantly upregulated in neurons. Here, we propose to study the impact of immune response genes on neuronal damage and to use this information to devise novel strategies to promote neuroprotection in the context of pathological inflammation. We hypothesize that suppressing immune-related gene expression programs in neurons will promote neuroprotection in the context of pathological inflammation.