PROJECT SUMMARY Multiple sclerosis (MS) is a highly disabling neurological disease affecting veterans, characterized by demyelination, inflammatory responses and neurodegeneration. Current medications available for treating MS are only partially effective as they specifically target the inflammatory phase, but not the neurodegenerative phase, and therefore have limited effects on long-term disability. Increasing evidences suggest that neurodegeneration plays a crucial role in the MS pathology. However, the mechanisms underlying the progressive neurodegeneration are poorly studied in MS. Hence, there is a great need for identifying new agents that target the neurodegenerative stage of the disease. Our goal is to contribute to the treatment of MS, by defining the specific role of Spermine Oxidase (SMOX, an important enzyme in polyamine metabolic pathway), in mediating neurodegeneration in the MS retina and by demonstrating its potential as a therapeutic target for MS treatment. Our central hypothesis is that SMOX is upregulated in retinal neurons, resulting in increased polyamine oxidation and release of acrolein in the MS retina. Our hypothesis predicts that formation of various protein-acrolein adducts causes oxidative damage in the retina, leading to neuronal dysfunction. Our objectives are: 1) characterize molecular mechanisms involved in SMOX-induced neuronal damage in the experimental model for MS; 2) determine the impact of SMOX overexpression/downregulation in mediating neurodegeneration in the experimental model of MS; and 3) determine the therapeutic potential of inhibiting SMOX for the treatment of MS. Our expected outcomes include 1) identification of SMOX induced molecular changes by which neuronal damage occurs in MS; 2) demonstration of alterations in retinal neuronal survival and function in response to manipulation of SMOX expression in the experimental model; and 3) preservation of visual acuity, contrast sensitivity, retinal structure and reduced inflammation in response to SMOX blockade. Our studies will impact the field of MS by providing new and significant information on mechanisms by which neurodegeneration occurs in MS, and thus can lead to the development of accurate and efficacious targeted therapies to improve the quality of life in veterans affected by the disease. Results coming out these studies may provide translational strategies for MS disease progression and can also be applicable to cognitive, behavioral and motor deficits in MS patients. Retina is known as “window to the brain” and hence targeting SMOX function has the potential to be evaluated as therapy for MS in general and is also applicable to other disabling diseases affecting veterans such as Traumatic brain injury, Parkinson’s disease and spinal cord injury.